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O-GlycNacylation Remission Retards the Progression of Non-Alcoholic Fatty Liver Disease

Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
The Second Clinical Medical College of Nanchang University, Nanchang 330031, China
Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
Authors to whom correspondence should be addressed.
Yunfeng Shen is the first corresponding author.
Cells 2022, 11(22), 3637;
Received: 13 October 2022 / Revised: 4 November 2022 / Accepted: 10 November 2022 / Published: 16 November 2022
(This article belongs to the Topic Inflammation: The Cause of All Diseases)


Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease spectrum associated with insulin resistance (IR), from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). O-GlcNAcylation is a posttranslational modification, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Abnormal O-GlcNAcylation plays a key role in IR, fat deposition, inflammatory injury, fibrosis, and tumorigenesis. However, the specific mechanisms and clinical treatments of O-GlcNAcylation and NAFLD are yet to be elucidated. The modification contributes to understanding the pathogenesis and development of NAFLD, thus clarifying the protective effect of O-GlcNAcylation inhibition on liver injury. In this review, the crucial role of O-GlcNAcylation in NAFLD (from NAFL to HCC) is discussed, and the effect of therapeutics on O-GlcNAcylation and its potential mechanisms on NAFLD have been highlighted. These inferences present novel insights into the pathogenesis and treatments of NAFLD.

1. Introduction

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome with excessive fat deposition in the hepatocytes [1]. It is closely associated with metabolic syndrome, obesity, insulin resistance (IR), and dyslipidemia. Due to the lack of obvious symptoms and starting with simple steatosis in most NAFLD patients, the disease is missed. However, a subset of NAFLD can develop into non-alcoholic steatohepatitis (NASH), and 20% of NASH patients progress to hepatic fibrosis. Once fibrosis occurs, a poor prognosis is developed, such as liver cirrhosis or hepatocellular carcinoma (HCC), the second-most common cause of cancer-related deaths [2]. Nowadays, with the abrupt rising of obesity and diabetes worldwide, the incidence of NAFLD has escalated rapidly [3], with a global prevalence of 25% [4]. Metabolic abnormalities are closely associated with NAFLD, and it was, hence, renamed “metabolic dysfunction-associated fatty liver disease” (MAFLD) in 2020 [5]. (For the convenience of its description, this article has used NAFLD). Moreover, NAFLD is associated with a metabolic imbalance in glucose, lipids, amino acids, bile acids, and iron [6]. Several recent studies have focused on the role of glucose or other metabolisms in NAFLD. Among these, hyperglycemia is a major influencing factor on NAFLD and stimulates insulin secretion and increases the synthesis of triglycerides in the liver. The excessive triglycerides accumulate gradually in the liver and are exported to generate hypertriglyceridemia [7]. In addition, long-term and chronic hyperglycemia-induced hepatocytes injury alters the structure and function of pancreatic β-cells and causes IR, thereby inducing and accelerating the occurrence and progression of NAFLD [8]. Glucose and fructose are the primary mediators of NAFLD, leading to triglyceride production [9]. Therefore, it is of great significance to elucidate the pathogenesis of NAFLD.
One hypothesis of NAFLD pathogenesis has been described by the “2-hit theory” [10], whereby the first hit of hepatic triglyceride accumulation (hepatic steatosis) is induced by IR facilitated by the liver metabolism of fructose. In the second hit, fructose promotes the fructosylation of proteins, the formation of reactive oxygen species (ROS), due to the molecular instability of its five-membered furanose ring [8], endoplasmic reticulum (ER) stress, and inflammation [11], which causes hepatocellular damage and eventually fibrosis [12]. Gradually, the “2-hit theory” has been modified into the “multiple parallel hits” hypothesis for NASH pathogenesis, suggesting that liver damage is caused by multiple parallel pathogenic events [13]. Recently, glycosylation, a posttranslational modification of the proteins in glucose metabolism, has been under intensive focus. The N-glycosylation on the specific peptide sites of serum proteins is a potential marker for the diagnosis of NAFLD-associated hepatocellular carcinoma (NAFLD-HCC) [14]. In addition, the N-glycosylation of the cyclic adenosine monophosphate (AMP)-responsive element-binding protein H (CREBH) improves lipid metabolism and alleviates NAFLD lipotoxicity [15]. Furthermore, some studies have indicated that protein O-GlcNAcylation differentially influences hepatic metabolism and fibrosis [16,17]. Polyphenolic compounds, such as silibinin and curcumin, have reduced NAFLD/NASH by inhibiting O-GlcNAcylation in mouse models [18,19]. Therefore, it can be inferred that O-GlcNAcylation plays a critical role in the pathogenesis of NAFLD.
The modification is also associated with various disorders related to abnormal glucose metabolism, including diabetic cardiomyopathy (DCM). Previous studies focused on the pathogenic mechanism of O-GlcNAcylation in DCM. Protein O-GlcNAcylation is significantly modified in the myocardium in diabetics and is a key regulator of the diabetic cardiac phenotype [20]. Mitigating this posttranslational protein modification improves DCM [21]. Interestingly, aberrant O-GlcNAcylation was detected in obesity, diabetes, cancer, and neurodegenerative diseases [22,23,24]. Also, the level of O-GlcNAcylation was upregulated in NASH mice [19]. In this review, O-GlcNAcylation in the pathogenesis of NAFLD is discussed and analyzed. Moreover, the application prospect of the intervention of O-GlcNAcylation in the treatment of NAFLD is reviewed for the first time.

2. Role of O-GlcNAc in Normal Liver Tissue

O-GlcNAcylation is a posttranslational modification requiring the attachment of a single O-linked β-N-acetylglucosamine (O-GlcNAc) moiety to the proteins [25,26,27]. The hexosamine biosynthetic pathway (HBP) regulates the O-GlcNAcylation levels. UDP-GlcNAc, a substrate for the protein O-GlcNAcylation, is produced in this process [28]. The two main enzymes involved in the regulation of protein O-GlcNAcylation modification are as follows: The O-GlcNAc transferase (OGT) catalyzes the transfer of a single N-acetylglucosamine to the proteins from UDP-GlcNAc, leading to their modification with the O-GlcNAc, and the single N-acetylglucosamine is hydrolyzed from the protein by O-GlcNAcase (OGA). O-GlcNAcylation has a reciprocal correlation with O-phosphorylation and modulates many biological processes in eukaryotes; thus, it is considered a critical regulatory modification [29].
O-GlcNAcylation is essential for maintaining the normal physiological homeostasis of the liver; studies have shown that modification acts as a metabolic sensor for liver clock regulation to maintain the circadian control of glucose [30,31]. Some studies have shown that O-GlcNAcylation plays a critical role in gluconeogenesis (Figure 1). The activity of peroxisome proliferator-activated receptor-γ co-activator1α (PGC1α) and FoxO1, key gluconeogenic regulators, is regulated by O-GlcNAcylation [32,33,34]. PGC1α, an essential coactivator of the transcriptional stimulation of gluconeogenic genes [35,36,37], further stimulates the expression of gluconeogenic genes. OGT affects PGC1α-mediated gluconeogenesis gene expression by targeting PGC1α via the host cell factor C1 (HCF-1) [34,35]. O-GlcNAcylation also stabilizes PGC1α by recruiting BAP1 for deubiquitination to promote gluconeogenesis [34]. PGC1α promotes OGT to effectuate O-GlcNAcylation and activate FoxO1 and increases the expression of Pepck and G6pc and the transcription of ROS detoxification enzymes, manganese superoxide dismutase (MnSOD) and catalase (CAT), further promoting hepatic glucose production [32]. OGT also increases the expression of Pepck and G6pc, which induces hepatic gluconeogenesis by the O-GlcNAcylation of the cAMP-regulated transcriptional co-activator 2 (CRTC2), a co-activator of the cyclic AMP-responsive element-binding protein (CREB) [38]. It has also been suggested that OGT is involved in glucocorticoid-induced gluconeogenesis [39]. p53 is usually recognized as a tumor suppressor [40]. A recent study reported that insulin sensitivity and liver glucose homeostasis are regulated by integrating the p53 signaling pathways, which depend on p53 O-GlcNAcylation. Subsequently, O-GlcNAcylated p53 binds to the PCK1 promoter to activate the gluconeogenic effect [41].
Furthermore, whether glucose flux promotes fat production through O-GlcNAcylation needed to be clarified. liver X receptors (LXRs) are lipid metabolism, glucose stability, and inflammation sensors. O-GlcNAcylation of the hepatic LXR was observed in refed mice and streptozotocin-induced diabetic mice [42]. High glucose increases the O-GlcNAcylation of the LXR and the transcriptional activity of the sterol regulatory element-binding protein 1 (SREBP-1) promoter. SREBP-1 is a master transcriptional regulator of hepatic lipogenesis [42], and the O-GlcNAcylation of the LXR upregulates the expression of SREBP-1 in the liver [42]. OGT regulates the phosphorylation and stability of SREBP-1 by increasing AMP-activated protein kinase (AMPK) O-GlcNAcylation in breast cancer [43], followed by the transcriptional activity of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). The carbohydrate-responsive element-binding protein (ChREBP) plays a vital role in glycolysis and lipogenesis. In hepatocytes, the O-GlcNAcylation of the ChREBP stabilizes the protein and increases its transcriptional activity on the target glycolysis [liver pyruvate kinase (L-PK)] and lipidogenic genes [ACC, FAS, and stearoyl-CoA desaturase1 (SCD1)] [44]. Therefore, exploring the mechanistic and kinetic characterization of O-GlcNAcylation on key signaling proteins is promising for an in-depth understanding of normal hepatic metabolism. Finally, some studies have shown that multiple nodes of the insulin signaling pathway were altered by OGT. Under normal physiological conditions, O-GlcNAcylation is responsible for insulin signaling transduction. However, it would be abnormally elevated and induce IR in the state of overnutrition.
Elevated O-GlcNAcylation is not entirely detrimental to the liver. The termination of defective liver regeneration leads to reduced hepatocyte redifferentiation, severe necroinflammation, early fibrotic changes, and the formation of dysplastic nodules leading to the development of hepatocellular carcinoma (HCC) [45]. HNF4a O-GlcNAcylation in hepatocytes plays a key role in the termination of liver regeneration and prevention of hepatic dysplasia [45]. Studies have confirmed that calcium-dependent O-GlcNAc signaling is also critical in driving hepatic autophagy to maintain a nutrient and energy balance in response to starvation [46]. In addition, O-GlcNAc maintains a normal mitochondrial function, and the long-term elevation of o-GlcNAacylation coupled with an increased OGA expression modulates the mitochondrial function and reduces antioxidant responses [47]. For other liver diseases, such as hepatitis B, O-GlcNAcylation promotes the autophagic degradation of hepatitis B virus (HBV) replication virions and proteins through the mTORC1 signaling pathway and autophagosome-lysosome fusion, resulting in reduced HBV replication [48].

3. O-GlcNAcylation Contributes to IR

The liver is an insulin-sensitive organ and essential for maintaining blood glucose. IR also plays a vital role in the occurrence and development of type 2 diabetes mellitus (T2DM) and NAFLD. Strikingly, NAFLD occurs in 70–80% of T2DM and obesity patients, and most NAFLD patients, develop hepatic IR [49]. The pathogenesis of NAFLD is closely related to IR as it is one of the components of the pathogenesis of NAFLD [50]. Additionally, IR is characterized by decreased glucose uptake and utilization in tissues, including liver tissue, adipose tissue, and muscle tissue [51]. IR increases the circulating free fatty acids through dysregulated lipolysis, resulting in an impaired insulin signal, a reduced clearance rate of glucose metabolism, and the dysregulation of lipid aggregation and decomposition [52]. In addition, the body increases lipid synthesis for energy by breaking down fat. Insulin increases lipase activity, thereby elevating the uptake of triglycerides by the adipose tissue and fat storage in the liver [53]. Lipid deposition in the liver further exacerbates IR. Preview studies demonstrated a critical role of O-GlcNAcylation in attenuating insulin signaling [49,50] (Figure 2).
A major mechanism for terminating insulin signaling is the inactivation of insulin receptor substrates. OGT inactivates the insulin signaling proteins, including insulin receptor substrate 1 (IRS-1), phosphatidylinositol-3-kinase (PI3K), phosphoinositide-dependent protein kinase 1 (PDK1), serine/threonine-protein kinase B (AKT), and protein tyrosine phosphatase 1B (PTP1B), promoting the attenuation of insulin signaling [50,51]. Interestingly, OGT uses IRS-1 as its direct substrate [54]. In 3T3-L1 adipocytes, the Tyr608 phosphorylation of IRS-1 is inhibited by elevated O-GlcNAcylation, thereby reducing AKT activity [54]. In addition, OGT also uses PDK1 and PI3K as direct substrates in insulin signal attenuation [54,55]. Decreased AKT activity is vital for terminating insulin signaling, and O-GlcNAcylation plays a key role in the regulation of AKT activity. Normal O-GlcNAcylation is valuable for AKT signal transduction, while the O-GlcNAcylation of Thr305/Thr312 disrupts the interaction between AKT and PDK1, resulting in the downregulation of AKT activity [56]. Then, the decreased AKT activity reduces glycogen synthesis via glycogen synthase kinase 3 beta (GSK3β) phosphorylation. GSKβ is modified by O-GlcNAcylation, after the inhibition of GSK3β by lithium, and the overall O-GlcNAcylation level is significantly increased [57]. However, the function of GSK3β O-GlcNAcylation needs further exploration. In addition, PTP1B controls hepatic insulin signaling by inhibiting PTP1B O-GlcNAcylation, improving insulin sensitivity, and reducing liver lipid deposition [58]. Another study found that the O-GlcNAcylation level of glycogen synthase (GS) is increased, and the activity of GS is decreased after high glucose or glucosamine treatment, thereby leading to IR [59]. Therefore, abnormal glycogenogenesis and gluconeogenesis are closely related to O-GlcNAcylation during the development of hepatic IR.

4. Association of O-GlcNAc with NAFLD Process

O-GlcNAcylation acts as a promoting factor throughout NAFL-NASH-liver fibrosis-HCC. The LXR and the ChREBP are directly modified by O-GlcNAcylation, and SREBP-1 is indirectly regulated by O-GlcNAcylation, resulting in liver fat deposition and NAFL formation [42,43,44] (Figure 3). During the progression of NAFL to NASH, O-GlcNAcylation modifies I6PK1 and the Nuclear factor-κB (NF-κB) subunit p65 to increase the inflammatory injury, while the NF-κB subunit c-Rel undergoes O-GlcNAcylation to exert an anti-inflammatory effect under hyperglycemic conditions [17,60,61]. Moreover, the O-GlcNAcylation of collagens accelerates fibrosis, while that of the serum response factor (SRF) has an antifibrotic effect [62,63]. It modifies the receptor-interacting protein kinase 3 (RIPK3) to induce NAFLD-HCC [64,65].

4.1. O-GlcNAc and NAFL

NAFLD is a generalized term encompassing a range of liver conditions of varying severities resulting in liver fibrosis [52]; a simple steatosis named NAFL resulted from triglyceride accumulation in the cytoplasm of hepatocytes. On the other hand, the ChREBP is a pivotal transcription factor mediating the effects of glucose on glycolysis and lipogenesis genes. A previous study showed that the ChREBP is a regulatory center of adipogenesis in vivo and plays a decisive role in developing hepatic steatosis and IR; the specific inhibition of the ChREBP significantly improves hepatic steatosis in ob/ob mice [66]. A further study demonstrated that O-GlcNAcylation stabilizes the ChREBP and increases the activity on glycolytic lipogenic genes (L-PK, ACC, FAS, and SCD1) [44] (Table 1). Importantly, the overexpression of OGT significantly increases the ChREBP in C57BL/6J mice liver, resulting in enhanced lipogenic gene expression and excess hepatic triglyceride deposition [44]. Furthermore, HCF-1 O-GlcNAcylation, in response to glucose or a high-carbohydrate diet (HCD), first recruited OGT to the ChREBP, which led to ChREBP O-GlcNAcylation and activation [67]. Whether the mechanism of O-GlcNAcylation regulates the ChREBP in HCD-induced NAFLD mice needs to be investigated further.
The level of SREBP-1, a transcription factor that activates FAS and ACC1, is elevated [68], accompanied by hepatic steatosis [69]. Mice with the liver-specific overexpression of mature human SREBP-1 develop hepatic lipid accumulation and feature a fatty liver by the age of 6 months [70]. A previous study demonstrated that excessive glucose promotes lipid accumulation by upregulating lipid genes, such as SREBP-1, FAS, and ACC1, in cultured hepatocytes and animal model liver tissues [71]. Previous studies have shown that SREBP-1 protein expression is regulated by O-GlcNAcylation [43]. Also, the overexpression of glutamine fructose-6-phosphate amidotransferase (GFAT) promotes lipid accumulation in hepatic cells as well as inflammatory pathway activation by increasing the ER stress by the HBP [72], which indicates a critical role of the HBP in thyroglobulin (TG) accumulation. However, an updated study did not observe the response of SREBP-1 O-GlcNAcylation to GFAT inhibitors [73]. The correlation between SREBP-1 and the HBP and whether SREBP-1 directly effectuates O-GlcNAcylation is yet to be elucidated.

4.2. O-GlcNAc and NASH

In the preliminary stage, most patients with NAFLD manifest as hepatic steatosis without any symptoms. As the disease progresses, a proportion of the patients show NASH with inflammatory manifestation, hepatocyte injury, and fibrosis [74]. Nevertheless, the molecular mechanisms underlying the development of NAFLD and NASH are poorly understood. Protein O-GlcNAcylation impedes insulin signaling and promotes adipogenesis [16]. A recent study showed that inositol hexakisphosphate kinases 1 (IP6K1) inhibitors improve metabolic disorders, NAFLD/NASH. and fibrosis by altering these pathways [17]. How IP6K1 stimulates the protein O-GlcNAcylation to improve NAFLD by knocking down OGT remains to be explored.
Previous studies have indicated that O-GlcNAcylation is upregulated in NASH mice; however, the causal correlation between the upregulation of O-GlcNAcylation and the pathology of NASH is unclear. NF-κB, a proinflammatory transcription, is related to many pathogenic liver diseases [75], and NF-κB activated by inositol requiring enzyme 1α (IRE1α) causes liver inflammation and promotes NASH [76,77]. In addition, the activity of NF-κB is regulated by O-GlcNAcylation [60], and the upregulated O-GlcNAcylation activates NF-κB and increases inflammatory damage [78].
ROS accumulation and related ER stresses are caused by fat toxicity [79,80]. The transcription of GTAT is upregulated under ER stress, increasing protein O-GlcNAcylation [81]. Another study showed that O-GlcNAcylation, OGT, and GFAT levels are increased in mice with a methionine-choline deficient (MCD) diet, and the upregulated OGT and GFAT originate from the upstream target IRE1α induced via ER stress [19]. Currently, transcription factor X-box-binding protein 1 (XBP1) is the only known transcription factor downstream of IRE1α [82], and a key transcription factor is involved in hepatic adipogenesis and inflammation through ER stress [83]. These studies suggested that the upstream activator of the HBP is regulated by the transcription of XBP1 and is a positive regulatory loop for the onset of NASH. In another study, the expression of fructose-1,6-bisphosphatase (FBPase) was upregulated in NASH mice, leading to elevated F6P levels, HBP flux, and upregulated O-GlcNAcylation [18]. The increased level of protein O-GlcNAcylation by elevating the HBP flux in the liver plays a critical role in establishing a correlation between the increase in liver FBPase and NASH [84].

4.3. O-GlcNAc and Hepatic Fibrosis

Hepatic fibrosis is the most critical predictor of mortality in NAFLD, and the risk of liver-associated mortality increases exponentially with the increase in the fibrosis stage [85]. NASH patients with liver fibrosis are prone to develop cirrhosis [86]. Currently, only a few studies are related to O-GlcNAcylation and liver fibrosis. Hepatic stellate cells (HSCs) are the major source of the extracellular matrix in the liver [87]. Activated HSCs contribute to fibrogenesis. Interestingly, O-GlcNAcylation is involved in activating HSCs and collagen expression [62]. HSC activation originates from FoxO1 inactivation, leading to NAFLD fibrosis [88]. Paradoxically, the expression and activity of FoxO1 are increased in NASH patients [89]. Since FoxO1 plays a critical role in fibrosis and could be O-GlcNAcylated, it is essential to elucidate the role of FoxO1 O-GlcNAacylation on liver fibrosis through gene knockdown.
It was found that OGT-deficient hepatocytes are prone to hepatocyte ballooning, inflammation, and liver fibrosis [65]. OGT, a negative regulator of HSC activation, exerts a protective effect against hepatic fibrosis by boosting SRF O-GlcNAcylation. Therefore, the OGT expression and O-GlcNAcylation were decreased in HSCs isolated from MCD-fed mice livers [63]. In contrast, a recent study reported that OGT-deficient necroptotic hepatocytes secrete trefoil factor 2 (TFF2), which induces HSC activation, proliferation, and migration via platelet-derived growth factor receptorβ (PDGFRβ) signaling [90]. Thus, it is essential to clarify whether O-GlcNAc could be used as a biomarker for liver disease.

4.4. O-GlcNAc and NAFLD-HCC

NAFLD is becoming the leading cause of HCCs. NAFLD/NASH-HCC incidence and mortality rates are rising worldwide [91]. Furthermore, a retrospective cohort study from 2002 to 2012 indicated that NASH-related HCC increased significantly, and the number of patients undergoing liver transplantation for HCCs secondary to NASH increased by nearly four-fold, while the number of patients with HCCs secondary to chronic hepatitis C virus (HCV) increases only by two-fold [92]. NAFLD-HCC patients exhibit upregulated levels of OGT, which plays an oncogenic role by activating the oncogenic c-jun N-terminal kinases (JNK)/c-Jun/AP-1 and nuclear factor-kappa B (NF-κB) cascades [93]. Another study demonstrated that OGT is a key inhibitor of hepatocyte necroptosis in alcoholic fatty liver disease, and the lack of O-GlcNAcylation induces necroptosis in hepatocytes [65]. However, the specific pathogenesis mechanisms of NAFLD-HCC have not yet been totally revealed.
The mutual inhibition of caspase 8 and RIPK3 is essential for the development of NASH and hepatocarcinogenesis [64,94], and RIPK3 prevents cell proliferation from limiting the development of HCCs by inhibiting caspase 8 cleavage and JNK activation [64]. A study discovered that O-GlcNAcylation inhibits RIPK3 protein expression and stability [65]. Further investigation would analyze the molecular mechanism underlying OGT-regulated-RIPK3 gene transcription by O-GlcNAcylation. Nonetheless, only a few studies have elaborated on the role of OGA in the liver. Targeting O-GlcNAcylation is a potential therapy for NAFLD-HCC.
Furthermore, OGT overexpression in the liver increased intracellular palmitic acid levels and promoted HCC by activating ER stress-associated oncogenic signaling cascades, including the JNK/c-Jun/AP1 and NF-κB signaling pathways [93]. Typically, 2/3 of NAFLD-HCC tumors show OGT overexpression, while 1/3 of no change in OGT expression is seen, suggesting that OGT expression is associated with gene polymorphism related to the occurrence and progression of NAFLD and NASH, such as PNOLA3 p.I148M, TM6SF2 p.E167K, and MBOAT7 rs641738 [95,96]. Further studies should investigate whether OGT has a prognostic value for NAFLD-HCC.

5. Drugs Ameliorates NAFLD through Inhibition of O-GlcNAcylation

Metformin (MET) inhibits the proliferation of cervical cancer cells by reducing the O-GlcNAcylation of AMPK and increasing the level of phospho-AMPK [97] (Table 2). Another study indicated that MET inhibits the O-GlcNAc modification of NF-κB p65 and the ChREBP in the diabetic retina [98]. In addition, MET has been shown to have a protective effect on NAFLD, but the specific mechanism is yet unclear [99]. Furthermore, O-GlcNAcylation is activated, and AMPK/ACC pathway phosphorylation is inhibited in high-fat diet (HFD)-fed mice [100]. It has also been suggested that MET reduces hepatic TG accumulation and improves obesity-related NAFLD by inhibiting hepatic apolipoprotein A5 (ApoA5) synthesis through the AMPK/LXRα signaling pathway [101]. Therefore, it was speculated that MET promotes AMPK phosphorylation in the NAFLD liver by regulating AMPK O-GlcNAcylation and inhibiting the O-GlcNAc modification of the ChREBP, further increasing fat mobilization and reducing fat deposition in the liver. Also, inflammatory damage is alleviated by inhibiting the O-GlcNAc modification of NF-κB p65 in NAFLD patients.
The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, improves NASH by lowering liver enzyme levels and reducing liver fat [103]. Also, liraglutide and semaglutide improved NASH in clinical trials [114,115]. Yu et al. [116] proposed that GLP-1 inhibits the activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome, and reduced the production of ROS by enhancing mitophagy in hepatocytes, eventually improving NAFLD and delaying the progression of NASH. In addition, the activity of GLP-1 was enhanced by the inhibition of proteolysis due to O-GlcNAcylation [102]. However, the mechanisms underlying the elevated protein O-GlcNAcylation induced by GLP-1 that alleviated NAFLD/NASH are yet to be elaborated.
Goldberg et al., and Park et al. [117,118] speculated that increased O-GlcNAcylation enhances the pro-fibrotic signaling in mesangial cells exposed to high glucose. Sodium-glucose cotransporter 2 inhibitor (SGLT-2i) exerts antifibrotic effects in the diabetic kidney by reducing protein O-GlcNacylation [104]. In a clinical study, NAFLD patients treated with SGLT-2i experienced a remission of hepatic steatosis and improvement in liver fibrosis [105]. Some animal studies have also shown improvements in hepatic steatosis and steatohepatitis with various SGLT-2is, including remogliflozin, luseogliflozin, empagliflozin (EMPA), ipragliflozin, and NGI001 [119,120,121,122,123,124]. EMPA attenuated NAFLD in HFD-fed mice by activating autophagy and reducing ER stress and apoptosis [125]. Another study suggested that EMPA significantly improves NAFLD-related liver injury by enhancing the autophagy of hepatic macrophages through the AMPK/mammalian target of the rapamycin (mTOR) signaling pathway and further inhibiting the interleukin (IL)-17/IL-23 axis-mediated inflammatory response [126]. Presumably, SGLT-2i exerts an antifibrotic effect in NAFLD patients by reducing the protein O-GlcNacylation. It also ameliorates NAFLD/NASH by reducing ER stress and activates hepatocyte autophagy by inhibiting O-GlcNacylation.
The positive cardiovascular and metabolic effects of angiotensin (Ang)-converting enzyme inhibitors (ACEIs) are mainly dependent on the reduction of AngII formation and the increase in the negatively regulated Ang 1-7 axis of the renin-angiotensin system (RAS) [127,128]. Some studies have shown that ACE/AngII/AT1 contributes to the occurrence and progression of NAFLD [129]. The activation of the ACE2/Ang-(1-7)/Mas axis ameliorates hepatic IR through the Akt/PI3K/IRS-1/JNK insulin signaling pathway [130]. Moreover, Ang1-7 contributes to the correction of diabetic retinopathy by reducing the O-GlcNAcylation of the retinal protein in HFD-fed mice through the Mas/EPAC/Rap1/OGT signaling axis [106]. Also, ACEI therapy has been shown to reduce the incidence of liver cancer and cirrhosis in NAFLD patients [107].
Acetaminophen (APAP) overdose is a common cause of acute liver failure (ALF) in North American and European countries [131,132]. The increase in the hepatic O-GlcNacylated protein leads to the dysregulation of the hepatic glutathione (GSH) supplement response and increases the APAP-induced hepatic injury, while reduced O-GlcNacylation causes rapid GSH replenishment and the subsequent inhibition of APAP-induced liver injury [133]. Increased hepatic O-GlcNacylation as a response to excessive APAP increases and delays JNK activation, which is correlated to pronounced liver damage [133]. Moreover, Chen et al. [108] displayed a positive correlation between O-GlcNacylated c-Jun and GSH synthesis in clinical liver cancer samples. The overexpression of O-GlcNAcylated c-Jun inhibits ferroptosis by inducing GSH synthesis and blocking c-Jun O-GlcNacylation, which is beneficial for the treatment of iron apoptosis-related HCC [108]. Also, oral GSH exhibits a therapeutic effect on NAFLD patients; however, the mechanisms are remained unknown [109].
Alpha-lipoic acid (ALA) protects the kidney from oxidative damage in diabetic rats by reducing the O-GlcNAcylation of ERK and p38 [110]. In another study, ALA slowed the development of diabetic complications and ensured the function and health of red blood cells by reducing the O-GlcNAcylation modification levels of antioxidant enzymes: CuZn-superoxide dismutase (SOD), CAT, heat shock protein (HSP) 70, and HSP 90 [111]. Furthermore, it confirmed that the O-GlcNAcylation of the thioredoxin interacting protein (TXNIP) activates the NLRP3 inflammasome by interacting with the NLRP3 [134]. In a clinical trial, ALA was demonstrated to improve IL-6 and serum adiponectin levels in NAFLD patients [135]. Recently, two studies showed that ALA attenuates hepatic triglyceride accumulation and NAFLD by inhibiting the NLRP3 inflammasome [112,113]. Whether ALA plays a crucial role in NAFLD by changing the total level of O-GlcNAcylation or directly reducing the O-GlcNAcylation of NLRP3 and the role of O-GlcNAcylation in NAFLD, although drugs such as ALA, GSH, and ACEI exert a protective effect through anti-inflammatory and antioxidant effects, are yet to be clarified.
Hitherto, the pharmacological treatment of NAFLD by directly inhibiting O-GlcNAc has rarely been studied. Lee et al., showed that curcumin regulates the expression of SIRT1 and SOD1 through O-GlcNAcylation signaling [19]. It also reduces hepatitis by blocking the HBP flux signaling pathway; the anti-inflammatory effect of curcumin was achieved by inhibiting O-GlcNAcylation and blocking the NF-κB signaling pathway [19]. Silibinin blocks the NF-κB signaling pathway by inhibiting O-GlcNAcylation and alleviates inflammation in NASH mice [18]. Therefore, additional drug studies are required to further explore the treatment of NAFLD/NASH by targeting O-GlcNAcylation.

6. Conclusions

In this study, elevated O-GlcNAcylation promoted the development and exacerbation of IR and was eventually involved in the progression of NAFL-NASH-cirrhosis-hepatoma tetralogy. In addition, the potential drugs targeted at O-GlcNAcylation in the NAFLD intervention were reviewed. Thus, elucidating the molecular mechanisms of O-GlcNAcylation provided additional strategies and ideas for preventing and treating NAFLD.

Author Contributions

Y.S. and P.Y.: study concept, design, methodology, and funding acquisition. Y.Z.: drafting of the manuscript, critical revision of the manuscript for important intellectual content, and validation. Z.L.: visualization, editing, and supervision. M.X., D.Z. and J.L.: acquisition of data, analysis, and interpretation of data. All authors have read and agreed to the published version of the manuscript.


This work was supported by the National Natural Science Foundation of China [grant number No.82160170 and No.81860151]; the National Key R&D Program of China, Synthetic Biology Research [No.2019YFA0904500]; the Key R&D Program of Jiangxi Province [No. 20192BBG70027]; the National Clinical Research Center for Geriatrics—JiangXi branch center [No. 2021ZDG02001]; [No. 20212BAB216047 and No. 202004BCJL23049], and the National Natural Science Foundation of China [grant number No. 82100869].


The graphical abstracts were created with BioRender software (

Conflicts of Interest

The authors declare no conflict of interest.


Ang angiotensin
APAP acetaminophen
ALF acute liver failure
ALA alpha-lipoic acid
ApoA5 apolipoprotein A5
ACC acetyl-CoA carboxylase
AMP adenosine monophosphate
AMPK AMP-activated protein kinase
AKT serine/threonine-protein kinase B
ACEI Angiotensin-converting enzyme inhibitors
CAT catalase
CRTC2 cAMP-regulated transcriptional co-activator 2
CREB cyclic AMP-responsive element-binding protein
CREBH cyclic AMP-responsive element-binding protein H
ChREBP carbohydrate-responsive element-binding protein
DCM diabetic cardiomyopathy
EMPA empagliflozin
ER endoplasmic reticulum
FAS fatty acid synthase
FBPase fructose-1,6-bisphosphatase
GSH glutathione
GS glycogen synthase
GLP-1 glucagon-like peptide-1
GSK3β glycogen synthase kinase 3 beta
GFATglutamine fructose-6-phosphate amidotransferase
HCV hepatitis C virus
HSP heat shock protein
HCF-1 host cell factor C1
HSCs hepatic stellate cells
HCD high-carbohydrate diet
HCC hepatocellular carcinoma
HBP hexosamine biosynthetic pathway
IL interleukin
IR insulin resistance
IRS-1 insulin receptor substrate 1
IRE1α inositol requiring enzyme 1α
IP6K1 inositol hexakisphosphate kinases 1
JNK Jun N-terminal kinases
LXRs liver X receptors
L-PK liver pyruvate kinase
MET metformin
MCD methionine-choline deficient
mTOR mammalian target of rapamycin
MnSOD manganese superoxide dismutase
MAFLD metabolic dysfunction-associated fatty liver disease
NASH non-alcoholic steatohepatitis
NAFLD non-alcoholic fatty liver disease
NLRP3 NLR family, pyrin domain containing 3
OGA GlcNAcase
OGT O-GlcNAc transferase
O-GlcNAc O-linked β-N-acetylglucosamine
PI3K phosphatidylinositol-3-kinase
PTP1B protein tyrosine phosphatase 1B
PDGFRβ platelet-derived growth factor receptorβ
PDK1 phosphoinositide-dependent protein kinase 1
PGC1α peroxisome proliferator-activated receptor-γ co-activator1α
ROS reactive oxygen species
RAS renin-angiotensin system
RIPK3 receptor-interacting protein kinase 3
SRF serum response factor
SOD superoxide dismutase
SCD1 stearoyl-CoA desaturase1
SGLT-2i sodium-glucose cotransporter 2 inhibitor
SREBP-1 sterol regulatory element-binding protein 1
TG thyroglobulin
TFF2 trefoil factor 2
T2DM type 2 diabetes mellitus
TXNIP thioredoxin interacting protein
XBP1 X-box-binding protein 1


  1. Angulo, P. Nonalcoholic fatty liver disease. N. Engl. J. Med. 2002, 346, 1221–1231. [Google Scholar] [CrossRef] [PubMed][Green Version]
  2. Khamphaya, T.; Chukijrungroat, N.; Saengsirisuwan, V.; Mitchell-Richards, K.A.; Robert, M.E.; Mennone, A.; Ananthanarayanan, M.; Nathanson, M.H.; Weerachayaphorn, J. Nonalcoholic fatty liver disease impairs expression of the type II inositol 1,4,5-trisphosphate receptor. Hepatology 2018, 67, 560–574. [Google Scholar] [CrossRef] [PubMed][Green Version]
  3. Allen, A.M.; Therneau, T.M.; Larson, J.J.; Coward, A.; Somers, V.K.; Kamath, P.S. Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: A 20 year-community study. Hepatology 2018, 67, 1726–1736. [Google Scholar] [CrossRef] [PubMed][Green Version]
  4. Cotter, T.G.; Rinella, M. Nonalcoholic Fatty Liver Disease 2020: The State of the Disease. Gastroenterology 2020, 158, 1851–1864. [Google Scholar] [CrossRef] [PubMed]
  5. Eslam, M.; Newsome, P.N.; Sarin, S.K.; Anstee, Q.M.; Targher, G.; Romero-Gomez, M.; Zelber-Sagi, S.; Wai-Sun Wong, V.; Dufour, J.F.; Schattenberg, J.M.; et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J. Hepatol. 2020, 73, 202–209. [Google Scholar] [CrossRef]
  6. Gawrieh, S.; Marion, M.C.; Komorowski, R.; Wallace, J.; Charlton, M.; Kissebah, A.; Langefeld, C.D.; Olivier, M. Genetic variation in the peroxisome proliferator activated receptor-gamma gene is associated with histologically advanced NAFLD. Dig. Dis. Sci. 2012, 57, 952–957. [Google Scholar] [CrossRef]
  7. Shao, M.; Ye, Z.; Qin, Y.; Wu, T. Abnormal metabolic processes involved in the pathogenesis of non-alcoholic fatty liver disease (Review). Exp. Ther. Med. 2020, 20, 26. [Google Scholar] [CrossRef]
  8. Lim, J.S.; Mietus-Snyder, M.; Valente, A.; Schwarz, J.M.; Lustig, R.H. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat. Rev. Gastroenterol. Hepatol. 2010, 7, 251–264. [Google Scholar] [CrossRef]
  9. Jensen, T.; Abdelmalek, M.F.; Sullivan, S.; Nadeau, K.J.; Green, M.; Roncal, C.; Nakagawa, T.; Kuwabara, M.; Sato, Y.; Kang, D.H.; et al. Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J. Hepatol. 2018, 68, 1063–1075. [Google Scholar] [CrossRef][Green Version]
  10. Browning, J.D.; Horton, J.D. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Investig. 2004, 114, 147–152. [Google Scholar] [CrossRef]
  11. Park, J.S.; Lee, D.H.; Lee, Y.S.; Oh, E.; Bae, K.H.; Oh, K.J.; Kim, H.; Bae, S.H. Dual roles of ULK1 (unc-51 like autophagy activating kinase 1) in cytoprotection against lipotoxicity. Autophagy 2020, 16, 86–105. [Google Scholar] [CrossRef]
  12. Navarro, L.A.; Wree, A.; Povero, D.; Berk, M.P.; Eguchi, A.; Ghosh, S.; Papouchado, B.G.; Erzurum, S.C.; Feldstein, A.E. Arginase 2 deficiency results in spontaneous steatohepatitis: A novel link between innate immune activation and hepatic de novo lipogenesis. J. Hepatol. 2015, 62, 412–420. [Google Scholar] [CrossRef][Green Version]
  13. Kim, S.H.; Kim, G.; Han, D.H.; Lee, M.; Kim, I.; Kim, B.; Kim, K.H.; Song, Y.M.; Yoo, J.E.; Wang, H.J.; et al. Ezetimibe ameliorates steatohepatitis via AMP activated protein kinase-TFEB-mediated activation of autophagy and NLRP3 inflammasome inhibition. Autophagy 2017, 13, 1767–1781. [Google Scholar] [CrossRef]
  14. Lin, Y.; Zhu, J.; Pan, L.; Zhang, J.; Tan, Z.; Olivares, J.; Singal, A.G.; Parikh, N.D.; Lubman, D.M. A Panel of Glycopeptides as Candidate Biomarkers for Early Diagnosis of NASH Hepatocellular Carcinoma Using a Stepped HCD Method and PRM Evaluation. J. Proteome Res. 2021, 20, 3278–3289. [Google Scholar] [CrossRef]
  15. Zhang, N.; Wang, Y.; Zhang, J.; Liu, B.; Deng, X.; Xin, S.; Xu, K. N-glycosylation of CREBH improves lipid metabolism and attenuates lipotoxicity in NAFLD by modulating PPARalpha and SCD-1. FASEB J. 2020, 34, 15338–15363. [Google Scholar] [CrossRef]
  16. Zhang, K.; Yin, R.; Yang, X. O-GlcNAc: A Bittersweet Switch in Liver. Front. Endocrinol. 2014, 5, 221. [Google Scholar] [CrossRef][Green Version]
  17. Mukherjee, S.; Chakraborty, M.; Ulmasov, B.; McCommis, K.; Zhang, J.; Carpenter, D.; Msengi, E.N.; Haubner, J.; Guo, C.; Pike, D.P.; et al. Pleiotropic actions of IP6K1 mediate hepatic metabolic dysfunction to promote nonalcoholic fatty liver disease and steatohepatitis. Mol. Metab. 2021, 54, 101364. [Google Scholar] [CrossRef]
  18. Lee, S.J.; Nam, M.J.; Lee, D.E.; Park, J.W.; Kang, B.S.; Lee, D.S.; Lee, H.S.; Kwon, O.S. Silibinin Ameliorates O-GlcNAcylation and Inflammation in a Mouse Model of Nonalcoholic Steatohepatitis. Int. J. Mol. Sci. 2018, 19, 2165. [Google Scholar] [CrossRef][Green Version]
  19. Lee, D.E.; Lee, S.J.; Kim, S.J.; Lee, H.S.; Kwon, O.S. Curcumin Ameliorates Nonalcoholic Fatty Liver Disease through Inhibition of O-GlcNAcylation. Nutrients 2019, 11, 2702. [Google Scholar] [CrossRef][Green Version]
  20. Prakoso, D.; Lim, S.Y.; Erickson, J.R.; Wallace, R.S.; Lees, J.G.; Tate, M.; Kiriazis, H.; Donner, D.G.; Henstridge, D.C.; Davey, J.R.; et al. Fine-tuning the cardiac O-GlcNAcylation regulatory enzymes governs the functional and structural phenotype of the diabetic heart. Cardiovasc. Res. 2022, 118, 212–225. [Google Scholar] [CrossRef]
  21. Qin, L.; Wang, J.; Zhao, R.; Zhang, X.; Mei, Y. Ginsenoside-Rb1 Improved Diabetic Cardiomyopathy through Regulating Calcium Signaling by Alleviating Protein O-GlcNAcylation. J. Agric. Food Chem. 2019, 67, 14074–14085. [Google Scholar] [CrossRef] [PubMed]
  22. Olivier-Van Stichelen, S.; Hanover, J.A. You are what you eat: O-linked N-acetylglucosamine in disease, development and epigenetics. Curr. Opin. Clin. Nutr. Metab. Care 2015, 18, 339–345. [Google Scholar] [CrossRef] [PubMed]
  23. Peterson, S.B.; Hart, G.W. New insights: A role for O-GlcNAcylation in diabetic complications. Crit. Rev. Biochem. Mol. Biol. 2016, 51, 150–161. [Google Scholar] [CrossRef] [PubMed]
  24. Wright, J.N.; Collins, H.E.; Wende, A.R.; Chatham, J.C. O-GlcNAcylation and cardiovascular disease. Biochem. Soc. Trans. 2017, 45, 545–553. [Google Scholar] [CrossRef]
  25. Bond, M.R.; Hanover, J.A. A little sugar goes a long way: The cell biology of O-GlcNAc. J. Cell Biol. 2015, 208, 869–880. [Google Scholar] [CrossRef][Green Version]
  26. Hardiville, S.; Hart, G.W. Nutrient regulation of gene expression by O-GlcNAcylation of chromatin. Curr. Opin. Chem. Biol. 2016, 33, 88–94. [Google Scholar] [CrossRef][Green Version]
  27. Yang, X.; Qian, K. Protein O-GlcNAcylation: Emerging mechanisms and functions. Nat. Rev. Mol. Cell Biol. 2017, 18, 452–465. [Google Scholar] [CrossRef][Green Version]
  28. Pekkurnaz, G.; Trinidad, J.C.; Wang, X.; Kong, D.; Schwarz, T.L. Glucose regulates mitochondrial motility via Milton modification by O-GlcNAc transferase. Cell 2014, 158, 54–68. [Google Scholar] [CrossRef][Green Version]
  29. Hart, G.W. Dynamic O-linked glycosylation of nuclear and cytoskeletal proteins. Annu. Rev. Biochem. 1997, 66, 315–335. [Google Scholar] [CrossRef]
  30. Kaasik, K.; Kivimae, S.; Allen, J.J.; Chalkley, R.J.; Huang, Y.; Baer, K.; Kissel, H.; Burlingame, A.L.; Shokat, K.M.; Ptacek, L.J.; et al. Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock. Cell Metab. 2013, 17, 291–302. [Google Scholar] [CrossRef]
  31. Li, M.D.; Ruan, H.B.; Hughes, M.E.; Lee, J.S.; Singh, J.P.; Jones, S.P.; Nitabach, M.N.; Yang, X. O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination. Cell Metab. 2013, 17, 303–310. [Google Scholar] [CrossRef] [PubMed][Green Version]
  32. Housley, M.P.; Udeshi, N.D.; Rodgers, J.T.; Shabanowitz, J.; Puigserver, P.; Hunt, D.F.; Hart, G.W. A PGC-1alpha-O-GlcNAc transferase complex regulates FoxO transcription factor activity in response to glucose. J. Biol. Chem. 2009, 284, 5148–5157. [Google Scholar] [CrossRef] [PubMed][Green Version]
  33. Housley, M.P.; Rodgers, J.T.; Udeshi, N.D.; Kelly, T.J.; Shabanowitz, J.; Hunt, D.F.; Puigserver, P.; Hart, G.W. O-GlcNAc regulates FoxO activation in response to glucose. J. Biol. Chem. 2008, 283, 16283–16292. [Google Scholar] [CrossRef] [PubMed][Green Version]
  34. Ruan, H.B.; Han, X.; Li, M.D.; Singh, J.P.; Qian, K.; Azarhoush, S.; Zhao, L.; Bennett, A.M.; Samuel, V.T.; Wu, J.; et al. O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1alpha stability. Cell Metab. 2012, 16, 226–237. [Google Scholar] [CrossRef] [PubMed][Green Version]
  35. Herzig, S.; Long, F.; Jhala, U.S.; Hedrick, S.; Quinn, R.; Bauer, A.; Rudolph, D.; Schutz, G.; Yoon, C.; Puigserver, P.; et al. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 2001, 413, 179–183. [Google Scholar] [CrossRef] [PubMed]
  36. Dominy, J.E., Jr.; Lee, Y.; Jedrychowski, M.P.; Chim, H.; Jurczak, M.J.; Camporez, J.P.; Ruan, H.B.; Feldman, J.; Pierce, K.; Mostoslavsky, R.; et al. The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Mol. Cell 2012, 48, 900–913. [Google Scholar] [CrossRef][Green Version]
  37. Wu, Z.; Jiao, P.; Huang, X.; Feng, B.; Feng, Y.; Yang, S.; Hwang, P.; Du, J.; Nie, Y.; Xiao, G.; et al. MAPK phosphatase-3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice. J. Clin. Investig. 2010, 120, 3901–3911. [Google Scholar] [CrossRef]
  38. Dentin, R.; Hedrick, S.; Xie, J.; Yates, J., 3rd; Montminy, M. Hepatic glucose sensing via the CREB coactivator CRTC2. Science 2008, 319, 1402–1405. [Google Scholar] [CrossRef]
  39. Li, M.D.; Ruan, H.B.; Singh, J.P.; Zhao, L.; Zhao, T.; Azarhoush, S.; Wu, J.; Evans, R.M.; Yang, X. O-GlcNAc transferase is involved in glucocorticoid receptor-mediated transrepression. J. Biol. Chem. 2012, 287, 12904–12912. [Google Scholar] [CrossRef][Green Version]
  40. Efeyan, A.; Serrano, M. p53: Guardian of the genome and policeman of the oncogenes. Cell Cycle 2007, 6, 1006–1010. [Google Scholar] [CrossRef]
  41. Gonzalez-Rellan, M.J.; Fondevila, M.F.; Fernandez, U.; Rodriguez, A.; Varela-Rey, M.; Veyrat-Durebex, C.; Seoane, S.; Bernardo, G.; Lopitz-Otsoa, F.; Fernandez-Ramos, D.; et al. O-GlcNAcylated p53 in the liver modulates hepatic glucose production. Nat. Commun. 2021, 12, 5068. [Google Scholar] [CrossRef]
  42. Anthonisen, E.H.; Berven, L.; Holm, S.; Nygard, M.; Nebb, H.I.; Gronning-Wang, L.M. Nuclear receptor liver X receptor is O-GlcNAc-modified in response to glucose. J. Biol. Chem. 2010, 285, 1607–1615. [Google Scholar] [CrossRef][Green Version]
  43. Sodi, V.L.; Bacigalupa, Z.A.; Ferrer, C.M.; Lee, J.V.; Gocal, W.A.; Mukhopadhyay, D.; Wellen, K.E.; Ivan, M.; Reginato, M.J. Nutrient sensor O-GlcNAc transferase controls cancer lipid metabolism via SREBP-1 regulation. Oncogene 2018, 37, 924–934. [Google Scholar] [CrossRef][Green Version]
  44. Guinez, C.; Filhoulaud, G.; Rayah-Benhamed, F.; Marmier, S.; Dubuquoy, C.; Dentin, R.; Moldes, M.; Burnol, A.F.; Yang, X.; Lefebvre, T.; et al. O-GlcNAcylation increases ChREBP protein content and transcriptional activity in the liver. Diabetes 2011, 60, 1399–1413. [Google Scholar] [CrossRef][Green Version]
  45. Robarts, D.R.; McGreal, S.R.; Umbaugh, D.S.; Parkes, W.S.; Kotulkar, M.; Abernathy, S.; Lee, N.; Jaeschke, H.; Gunewardena, S.; Whelan, S.A.; et al. Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice. Cell. Mol. Gastroenterol. Hepatol. 2022, 13, 1510–1529. [Google Scholar] [CrossRef]
  46. Ruan, H.B.; Ma, Y.; Torres, S.; Zhang, B.; Feriod, C.; Heck, R.M.; Qian, K.; Fu, M.; Li, X.; Nathanson, M.H.; et al. Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation. Genes Dev. 2017, 31, 1655–1665. [Google Scholar] [CrossRef][Green Version]
  47. Tan, E.P.; McGreal, S.R.; Graw, S.; Tessman, R.; Koppel, S.J.; Dhakal, P.; Zhang, Z.; Machacek, M.; Zachara, N.E.; Koestler, D.C.; et al. Sustained O-GlcNAcylation reprograms mitochondrial function to regulate energy metabolism. J. Biol. Chem. 2017, 292, 14940–14962. [Google Scholar] [CrossRef][Green Version]
  48. Wang, X.; Lin, Y.; Liu, S.; Zhu, Y.; Lu, K.; Broering, R.; Lu, M. O-GlcNAcylation modulates HBV replication through regulating cellular autophagy at multiple levels. FASEB J. 2020, 34, 14473–14489. [Google Scholar] [CrossRef]
  49. Tolman, K.G.; Fonseca, V.; Dalpiaz, A.; Tan, M.H. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care 2007, 30, 734–743. [Google Scholar] [CrossRef][Green Version]
  50. Choudhury, J.; Sanyal, A.J. Insulin resistance and the pathogenesis of nonalcoholic fatty liver disease. Clin. Liver Dis. 2004, 8, 575–594. [Google Scholar] [CrossRef]
  51. Bugianesi, E.; McCullough, A.J.; Marchesini, G. Insulin resistance: A metabolic pathway to chronic liver disease. Hepatology 2005, 42, 987–1000. [Google Scholar] [CrossRef] [PubMed]
  52. Friedman, S.L.; Neuschwander-Tetri, B.A.; Rinella, M.; Sanyal, A.J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 2018, 24, 908–922. [Google Scholar] [CrossRef] [PubMed]
  53. Schuster, S.; Cabrera, D.; Arrese, M.; Feldstein, A.E. Triggering and resolution of inflammation in NASH. Nat. Rev. Gastroenterol. Hepatol. 2018, 15, 349–364. [Google Scholar] [CrossRef] [PubMed]
  54. Whelan, S.A.; Dias, W.B.; Thiruneelakantapillai, L.; Lane, M.D.; Hart, G.W. Regulation of insulin receptor substrate 1 (IRS-1)/AKT kinase-mediated insulin signaling by O-Linked beta-N-acetylglucosamine in 3T3-L1 adipocytes. J. Biol. Chem. 2010, 285, 5204–5211. [Google Scholar] [CrossRef] [PubMed][Green Version]
  55. Whelan, S.A.; Lane, M.D.; Hart, G.W. Regulation of the O-linked beta-N-acetylglucosamine transferase by insulin signaling. J. Biol. Chem. 2008, 283, 21411–21417. [Google Scholar] [CrossRef][Green Version]
  56. Wang, S.; Huang, X.; Sun, D.; Xin, X.; Pan, Q.; Peng, S.; Liang, Z.; Luo, C.; Yang, Y.; Jiang, H.; et al. Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates Akt signaling. PLoS ONE 2012, 7, e37427. [Google Scholar] [CrossRef][Green Version]
  57. Wang, Z.; Pandey, A.; Hart, G.W. Dynamic interplay between O-linked N-acetylglucosaminylation and glycogen synthase kinase-3-dependent phosphorylation. Mol. Cell. Proteom. 2007, 6, 1365–1379. [Google Scholar] [CrossRef][Green Version]
  58. Zhao, Y.; Tang, Z.; Shen, A.; Tao, T.; Wan, C.; Zhu, X.; Huang, J.; Zhang, W.; Xia, N.; Wang, S.; et al. The Role of PTP1B O-GlcNAcylation in Hepatic Insulin Resistance. Int. J. Mol. Sci. 2015, 16, 22856–22869. [Google Scholar] [CrossRef][Green Version]
  59. Parker, G.J.; Lund, K.C.; Taylor, R.P.; McClain, D.A. Insulin resistance of glycogen synthase mediated by o-linked N-acetylglucosamine. J. Biol. Chem. 2003, 278, 10022–10027. [Google Scholar] [CrossRef][Green Version]
  60. Yang, W.H.; Park, S.Y.; Nam, H.W.; Kim, D.H.; Kang, J.G.; Kang, E.S.; Kim, Y.S.; Lee, H.C.; Kim, K.S.; Cho, J.W. NFkappaB activation is associated with its O-GlcNAcylation state under hyperglycemic conditions. Proc. Natl. Acad. Sci. USA 2008, 105, 17345–17350. [Google Scholar] [CrossRef]
  61. Ramakrishnan, P.; Clark, P.M.; Mason, D.E.; Peters, E.C.; Hsieh-Wilson, L.C.; Baltimore, D. Activation of the transcriptional function of the NF-kappaB protein c-Rel by O-GlcNAc glycosylation. Sci. Signal. 2013, 6, ra75. [Google Scholar] [CrossRef][Green Version]
  62. Fan, X.; Chuan, S.; Hongshan, W. Protein O glycosylation regulates activation of hepatic stellate cells. Inflammation 2013, 36, 1248–1252. [Google Scholar] [CrossRef]
  63. Li, R.; Ong, Q.; Wong, C.C.; Chu, E.S.H.; Sung, J.J.Y.; Yang, X.; Yu, J. O-GlcNAcylation inhibits hepatic stellate cell activation. J. Gastroenterol. Hepatol. 2021, 36, 3477–3486. [Google Scholar] [CrossRef]
  64. Vucur, M.; Reisinger, F.; Gautheron, J.; Janssen, J.; Roderburg, C.; Cardenas, D.V.; Kreggenwinkel, K.; Koppe, C.; Hammerich, L.; Hakem, R.; et al. RIP3 inhibits inflammatory hepatocarcinogenesis but promotes cholestasis by controlling caspase-8- and JNK-dependent compensatory cell proliferation. Cell Rep. 2013, 4, 776–790. [Google Scholar] [CrossRef][Green Version]
  65. Zhang, B.; Li, M.D.; Yin, R.; Liu, Y.; Yang, Y.; Mitchell-Richards, K.A.; Nam, J.H.; Li, R.; Wang, L.; Iwakiri, Y.; et al. O-GlcNAc transferase suppresses necroptosis and liver fibrosis. JCI Insight 2019, 4, e127709. [Google Scholar] [CrossRef][Green Version]
  66. Dentin, R.; Benhamed, F.; Hainault, I.; Fauveau, V.; Foufelle, F.; Dyck, J.R.; Girard, J.; Postic, C. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes 2006, 55, 2159–2170. [Google Scholar] [CrossRef][Green Version]
  67. Lane, E.A.; Choi, D.W.; Garcia-Haro, L.; Levine, Z.G.; Tedoldi, M.; Walker, S.; Danial, N.N. HCF-1 Regulates De Novo Lipogenesis through a Nutrient-Sensitive Complex with ChREBP. Mol. Cell 2019, 75, 357–371.e7. [Google Scholar] [CrossRef]
  68. Horton, J.D.; Goldstein, J.L.; Brown, M.S. SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Investig. 2002, 109, 1125–1131. [Google Scholar] [CrossRef]
  69. Kawano, Y.; Cohen, D.E. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J. Gastroenterol. 2013, 48, 434–441. [Google Scholar] [CrossRef][Green Version]
  70. Knebel, B.; Haas, J.; Hartwig, S.; Jacob, S.; Kollmer, C.; Nitzgen, U.; Muller-Wieland, D.; Kotzka, J. Liver-specific expression of transcriptionally active SREBP-1c is associated with fatty liver and increased visceral fat mass. PLoS ONE 2012, 7, e31812. [Google Scholar] [CrossRef]
  71. Gorgani-Firuzjaee, S.; Meshkani, R. SH2 domain-containing inositol 5-phosphatase (SHIP2) inhibition ameliorates high glucose-induced de-novo lipogenesis and VLDL production through regulating AMPK/mTOR/SREBP1 pathway and ROS production in HepG2 cells. Free Radic. Biol. Med. 2015, 89, 679–689. [Google Scholar] [CrossRef] [PubMed][Green Version]
  72. Sage, A.T.; Walter, L.A.; Shi, Y.; Khan, M.I.; Kaneto, H.; Capretta, A.; Werstuck, G.H. Hexosamine biosynthesis pathway flux promotes endoplasmic reticulum stress, lipid accumulation, and inflammatory gene expression in hepatic cells. Am. J. Physiol. Endocrinol. Metab. 2010, 298, E499–E511. [Google Scholar] [CrossRef] [PubMed]
  73. Park, J.; Lee, Y.; Jung, E.H.; Kim, S.M.; Cho, H.; Han, I.O. Glucosamine regulates hepatic lipid accumulation by sensing glucose levels or feeding states of normal and excess. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2020, 1865, 158764. [Google Scholar] [CrossRef] [PubMed]
  74. Kleiner, D.E.; Brunt, E.M.; Van Natta, M.; Behling, C.; Contos, M.J.; Cummings, O.W.; Ferrell, L.D.; Liu, Y.C.; Torbenson, M.S.; Unalp-Arida, A.; et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005, 41, 1313–1321. [Google Scholar] [CrossRef] [PubMed]
  75. Elsharkawy, A.M.; Mann, D.A. Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis. Hepatology 2007, 46, 590–597. [Google Scholar] [CrossRef]
  76. Malhi, H.; Kaufman, R.J. Endoplasmic reticulum stress in liver disease. J. Hepatol. 2011, 54, 795–809. [Google Scholar] [CrossRef][Green Version]
  77. Lake, A.D.; Novak, P.; Hardwick, R.N.; Flores-Keown, B.; Zhao, F.; Klimecki, W.T.; Cherrington, N.J. The adaptive endoplasmic reticulum stress response to lipotoxicity in progressive human nonalcoholic fatty liver disease. Toxicol. Sci. 2014, 137, 26–35. [Google Scholar] [CrossRef][Green Version]
  78. Baudoin, L.; Issad, T. O-GlcNAcylation and Inflammation: A Vast Territory to Explore. Front. Endocrinol. 2014, 5, 235. [Google Scholar] [CrossRef][Green Version]
  79. Ron, D.; Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 2007, 8, 519–529. [Google Scholar] [CrossRef]
  80. Ni, M.; Zhang, Y.; Lee, A.S. Beyond the endoplasmic reticulum: Atypical GRP78 in cell viability, signalling and therapeutic targeting. Biochem. J. 2011, 434, 181–188. [Google Scholar] [CrossRef]
  81. Ngoh, G.A.; Hamid, T.; Prabhu, S.D.; Jones, S.P. O-GlcNAc signaling attenuates ER stress-induced cardiomyocyte death. Am. J. Physiol. Heart Circ. Physiol. 2009, 297, H1711–H1719. [Google Scholar] [CrossRef][Green Version]
  82. So, J.S.; Hur, K.Y.; Tarrio, M.; Ruda, V.; Frank-Kamenetsky, M.; Fitzgerald, K.; Koteliansky, V.; Lichtman, A.H.; Iwawaki, T.; Glimcher, L.H.; et al. Silencing of lipid metabolism genes through IRE1alpha-mediated mRNA decay lowers plasma lipids in mice. Cell Metab. 2012, 16, 487–499. [Google Scholar] [CrossRef][Green Version]
  83. Kim, I.; Xu, W.; Reed, J.C. Cell death and endoplasmic reticulum stress: Disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov. 2008, 7, 1013–1030. [Google Scholar] [CrossRef]
  84. Visinoni, S.; Khalid, N.F.; Joannides, C.N.; Shulkes, A.; Yim, M.; Whitehead, J.; Tiganis, T.; Lamont, B.J.; Favaloro, J.M.; Proietto, J.; et al. The role of liver fructose-1,6-bisphosphatase in regulating appetite and adiposity. Diabetes 2012, 61, 1122–1132. [Google Scholar] [CrossRef][Green Version]
  85. Dulai, P.S.; Singh, S.; Patel, J.; Soni, M.; Prokop, L.J.; Younossi, Z.; Sebastiani, G.; Ekstedt, M.; Hagstrom, H.; Nasr, P.; et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology 2017, 65, 1557–1565. [Google Scholar] [CrossRef][Green Version]
  86. Hui, J.M.; Kench, J.G.; Chitturi, S.; Sud, A.; Farrell, G.C.; Byth, K.; Hall, P.; Khan, M.; George, J. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology 2003, 38, 420–427. [Google Scholar] [CrossRef][Green Version]
  87. Pinzani, M.; Rombouts, K. Liver fibrosis: From the bench to clinical targets. Dig. Liver Dis. 2004, 36, 231–242. [Google Scholar] [CrossRef]
  88. Adachi, M.; Osawa, Y.; Uchinami, H.; Kitamura, T.; Accili, D.; Brenner, D.A. The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells. Gastroenterology 2007, 132, 1434–1446. [Google Scholar] [CrossRef][Green Version]
  89. Valenti, L.; Rametta, R.; Dongiovanni, P.; Maggioni, M.; Fracanzani, A.L.; Zappa, M.; Lattuada, E.; Roviaro, G.; Fargion, S. Increased expression and activity of the transcription factor FOXO1 in nonalcoholic steatohepatitis. Diabetes 2008, 57, 1355–1362. [Google Scholar] [CrossRef][Green Version]
  90. Zhang, B.; Lapenta, K.; Wang, Q.; Nam, J.H.; Chung, D.; Robert, M.E.; Nathanson, M.H.; Yang, X. Trefoil factor 2 secreted from damaged hepatocytes activates hepatic stellate cells to induce fibrogenesis. J. Biol. Chem. 2021, 297, 100887. [Google Scholar] [CrossRef]
  91. Paik, J.M.; Golabi, P.; Younossi, Y.; Mishra, A.; Younossi, Z.M. Changes in the Global Burden of Chronic Liver Diseases from 2012 to 2017: The Growing Impact of NAFLD. Hepatology 2020, 72, 1605–1616. [Google Scholar] [CrossRef] [PubMed]
  92. Wong, R.J.; Cheung, R.; Ahmed, A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology 2014, 59, 2188–2195. [Google Scholar] [CrossRef] [PubMed]
  93. Xu, W.; Zhang, X.; Wu, J.L.; Fu, L.; Liu, K.; Liu, D.; Chen, G.G.; Lai, P.B.; Wong, N.; Yu, J. O-GlcNAc transferase promotes fatty liver-associated liver cancer through inducing palmitic acid and activating endoplasmic reticulum stress. J. Hepatol. 2017, 67, 310–320. [Google Scholar] [CrossRef] [PubMed][Green Version]
  94. Gautheron, J.; Vucur, M.; Reisinger, F.; Cardenas, D.V.; Roderburg, C.; Koppe, C.; Kreggenwinkel, K.; Schneider, A.T.; Bartneck, M.; Neumann, U.P.; et al. A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis. EMBO Mol. Med. 2014, 6, 1062–1074. [Google Scholar] [CrossRef] [PubMed]
  95. Krawczyk, M.; Jimenez-Aguero, R.; Alustiza, J.M.; Emparanza, J.I.; Perugorria, M.J.; Bujanda, L.; Lammert, F.; Banales, J.M. PNPLA3 p.I148M variant is associated with greater reduction of liver fat content after bariatric surgery. Surg. Obes. Relat. Dis. 2016, 12, 1838–1846. [Google Scholar] [CrossRef]
  96. Miyaaki, H.; Nakao, K. Significance of genetic polymorphisms in patients with nonalcoholic fatty liver disease. Clin. J. Gastroenterol. 2017, 10, 201–207. [Google Scholar] [CrossRef][Green Version]
  97. Kim, M.Y.; Kim, Y.S.; Kim, M.; Choi, M.Y.; Roh, G.S.; Lee, D.H.; Kim, H.J.; Kang, S.S.; Cho, G.J.; Shin, J.K.; et al. Metformin inhibits cervical cancer cell proliferation via decreased AMPK O-GlcNAcylation. Anim. Cells Syst. 2019, 23, 302–309. [Google Scholar] [CrossRef][Green Version]
  98. Kim, Y.S.; Kim, M.; Choi, M.Y.; Lee, D.H.; Roh, G.S.; Kim, H.J.; Kang, S.S.; Cho, G.J.; Kim, S.J.; Yoo, J.M.; et al. Metformin protects against retinal cell death in diabetic mice. Biochem. Biophys. Res. Commun. 2017, 492, 397–403. [Google Scholar] [CrossRef]
  99. Barbero-Becerra, V.J.; Santiago-Hernandez, J.J.; Villegas-Lopez, F.A.; Mendez-Sanchez, N.; Uribe, M.; Chavez-Tapia, N.C. Mechanisms involved in the protective effects of metformin against nonalcoholic fatty liver disease. Curr. Med. Chem. 2012, 19, 2918–2923. [Google Scholar] [CrossRef]
  100. Pang, Y.; Xu, X.; Xiang, X.; Li, Y.; Zhao, Z.; Li, J.; Gao, S.; Liu, Q.; Mai, K.; Ai, Q. High Fat Activates O-GlcNAcylation and Affects AMPK/ACC Pathway to Regulate Lipid Metabolism. Nutrients 2021, 13, 1740. [Google Scholar] [CrossRef]
  101. Lin, M.J.; Dai, W.; Scott, M.J.; Li, R.; Zhang, Y.Q.; Yang, Y.; Chen, L.Z.; Huang, X.S. Metformin improves nonalcoholic fatty liver disease in obese mice via down-regulation of apolipoprotein A5 as part of the AMPK/LXRalpha signaling pathway. Oncotarget 2017, 8, 108802–108809. [Google Scholar] [CrossRef][Green Version]
  102. Levine, P.M.; Balana, A.T.; Sturchler, E.; Koole, C.; Noda, H.; Zarzycka, B.; Daley, E.J.; Truong, T.T.; Katritch, V.; Gardella, T.J.; et al. O-GlcNAc Engineering of GPCR Peptide-Agonists Improves Their Stability and in Vivo Activity. J. Am. Chem. Soc. 2019, 141, 14210–14219. [Google Scholar] [CrossRef]
  103. Cusi, K. Incretin-Based Therapies for the Management of Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes. Hepatology 2019, 69, 2318–2322. [Google Scholar] [CrossRef]
  104. Hodrea, J.; Balogh, D.B.; Hosszu, A.; Lenart, L.; Besztercei, B.; Koszegi, S.; Sparding, N.; Genovese, F.; Wagner, L.J.; Szabo, A.J.; et al. Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney. Am. J. Physiol. Ren. Physiol. 2020, 318, F1017–F1029. [Google Scholar] [CrossRef]
  105. Akuta, N.; Watanabe, C.; Kawamura, Y.; Arase, Y.; Saitoh, S.; Fujiyama, S.; Sezaki, H.; Hosaka, T.; Kobayashi, M.; Kobayashi, M.; et al. Effects of a sodium-glucose cotransporter 2 inhibitor in nonalcoholic fatty liver disease complicated by diabetes mellitus: Preliminary prospective study based on serial liver biopsies. Hepatol. Commun. 2017, 1, 46–52. [Google Scholar] [CrossRef][Green Version]
  106. Dierschke, S.K.; Toro, A.L.; Barber, A.J.; Arnold, A.C.; Dennis, M.D. Angiotensin-(1-7) Attenuates Protein O-GlcNAcylation in the Retina by EPAC/Rap1-Dependent Inhibition of O-GlcNAc Transferase. Investig. Ophthalmol. Vis. Sci. 2020, 61, 24. [Google Scholar] [CrossRef][Green Version]
  107. Zhang, X.; Wong, G.L.; Yip, T.C.; Tse, Y.K.; Liang, L.Y.; Hui, V.W.; Lin, H.; Li, G.L.; Lai, J.C.; Chan, H.L.; et al. Angiotensin-converting enzyme inhibitors prevent liver-related events in nonalcoholic fatty liver disease. Hepatology 2022, 76, 469–482. [Google Scholar] [CrossRef]
  108. Chen, Y.; Zhu, G.; Liu, Y.; Wu, Q.; Zhang, X.; Bian, Z.; Zhang, Y.; Pan, Q.; Sun, F. O-GlcNAcylated c-Jun antagonizes ferroptosis via inhibiting GSH synthesis in liver cancer. Cell Signal. 2019, 63, 109384. [Google Scholar] [CrossRef]
  109. Honda, Y.; Kessoku, T.; Sumida, Y.; Kobayashi, T.; Kato, T.; Ogawa, Y.; Tomeno, W.; Imajo, K.; Fujita, K.; Yoneda, M.; et al. Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: An open-label, single-arm, multicenter, pilot study. BMC Gastroenterol. 2017, 17, 96. [Google Scholar] [CrossRef]
  110. Arambasic, J.; Mihailovic, M.; Uskokovic, A.; Dinic, S.; Grdovic, N.; Markovic, J.; Poznanovic, G.; Bajec, D.; Vidakovic, M. Alpha-lipoic acid upregulates antioxidant enzyme gene expression and enzymatic activity in diabetic rat kidneys through an O-GlcNAc-dependent mechanism. Eur. J. Nutr. 2013, 52, 1461–1473. [Google Scholar] [CrossRef]
  111. Mirjana, M.; Jelena, A.; Aleksandra, U.; Svetlana, D.; Nevena, G.; Jelena, M.; Goran, P.; Melita, V. Alpha-lipoic acid preserves the structural and functional integrity of red blood cells by adjusting the redox disturbance and decreasing O-GlcNAc modifications of antioxidant enzymes and heat shock proteins in diabetic rats. Eur. J. Nutr. 2012, 51, 975–986. [Google Scholar] [CrossRef] [PubMed]
  112. Ko, C.Y.; Lo, Y.M.; Xu, J.H.; Chang, W.C.; Huang, D.W.; Wu, J.S.; Yang, C.H.; Huang, W.C.; Shen, S.C. Alpha-lipoic acid alleviates NAFLD and triglyceride accumulation in liver via modulating hepatic NLRP3 inflammasome activation pathway in type 2 diabetic rats. Food Sci. Nutr. 2021, 9, 2733–2742. [Google Scholar] [CrossRef] [PubMed]
  113. Rahmanabadi, A.; Mahboob, S.; Amirkhizi, F.; Hosseinpour-Arjmand, S.; Ebrahimi-Mameghani, M. Oral alpha-lipoic acid supplementation in patients with non-alcoholic fatty liver disease: Effects on adipokines and liver histology features. Food Funct. 2019, 10, 4941–4952. [Google Scholar] [CrossRef] [PubMed]
  114. Armstrong, M.J.; Gaunt, P.; Aithal, G.P.; Barton, D.; Hull, D.; Parker, R.; Hazlehurst, J.M.; Guo, K.; LEAN Trial Team; Abouda, G.; et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): A multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016, 387, 679–690. [Google Scholar] [CrossRef][Green Version]
  115. Newsome, P.N.; Buchholtz, K.; Cusi, K.; Linder, M.; Okanoue, T.; Ratziu, V.; Sanyal, A.J.; Sejling, A.S.; Harrison, S.A.; Investigators, N.N. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N. Engl. J. Med. 2021, 384, 1113–1124. [Google Scholar] [CrossRef]
  116. Yu, X.; Hao, M.; Liu, Y.; Ma, X.; Lin, W.; Xu, Q.; Zhou, H.; Shao, N.; Kuang, H. Liraglutide ameliorates non-alcoholic steatohepatitis by inhibiting NLRP3 inflammasome and pyroptosis activation via mitophagy. Eur. J. Pharmacol. 2019, 864, 172715. [Google Scholar] [CrossRef]
  117. Goldberg, H.; Whiteside, C.; Fantus, I.G. O-linked beta-N-acetylglucosamine supports p38 MAPK activation by high glucose in glomerular mesangial cells. Am. J. Physiol. Endocrinol. Metab. 2011, 301, E713–E726. [Google Scholar] [CrossRef][Green Version]
  118. Park, M.J.; Kim, D.I.; Lim, S.K.; Choi, J.H.; Han, H.J.; Yoon, K.C.; Park, S.H. High glucose-induced O-GlcNAcylated carbohydrate response element-binding protein (ChREBP) mediates mesangial cell lipogenesis and fibrosis: The possible role in the development of diabetic nephropathy. J. Biol. Chem. 2014, 289, 13519–13530. [Google Scholar] [CrossRef][Green Version]
  119. Nakano, S.; Katsuno, K.; Isaji, M.; Nagasawa, T.; Buehrer, B.; Walker, S.; Wilkison, W.O.; Cheatham, B. Remogliflozin Etabonate Improves Fatty Liver Disease in Diet-Induced Obese Male Mice. J. Clin. Exp. Hepatol. 2015, 5, 190–198. [Google Scholar] [CrossRef][Green Version]
  120. Qiang, S.; Nakatsu, Y.; Seno, Y.; Fujishiro, M.; Sakoda, H.; Kushiyama, A.; Mori, K.; Matsunaga, Y.; Yamamotoya, T.; Kamata, H.; et al. Treatment with the SGLT2 inhibitor luseogliflozin improves nonalcoholic steatohepatitis in a rodent model with diabetes mellitus. Diabetol. Metab. Syndr. 2015, 7, 104. [Google Scholar] [CrossRef]
  121. Jojima, T.; Tomotsune, T.; Iijima, T.; Akimoto, K.; Suzuki, K.; Aso, Y. Empagliflozin (an SGLT2 inhibitor), alone or in combination with linagliptin (a DPP-4 inhibitor), prevents steatohepatitis in a novel mouse model of non-alcoholic steatohepatitis and diabetes. Diabetol. Metab. Syndr. 2016, 8, 45. [Google Scholar] [CrossRef][Green Version]
  122. Petito-da-Silva, T.I.; Souza-Mello, V.; Barbosa-da-Silva, S. Empaglifozin mitigates NAFLD in high-fat-fed mice by alleviating insulin resistance, lipogenesis and ER stress. Mol. Cell. Endocrinol. 2019, 498, 110539. [Google Scholar] [CrossRef]
  123. Tahara, A.; Takasu, T. SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone prevents progression of nonalcoholic steatohepatitis in a type 2 diabetes rodent model. Physiol. Rep. 2019, 7, e14286. [Google Scholar] [CrossRef][Green Version]
  124. Chiang, H.; Lee, J.C.; Huang, H.C.; Huang, H.; Liu, H.K.; Huang, C. Delayed intervention with a novel SGLT2 inhibitor NGI001 suppresses diet-induced metabolic dysfunction and non-alcoholic fatty liver disease in mice. Br. J. Pharmacol. 2020, 177, 239–253. [Google Scholar] [CrossRef][Green Version]
  125. Nasiri-Ansari, N.; Nikolopoulou, C.; Papoutsi, K.; Kyrou, I.; Mantzoros, C.S.; Kyriakopoulos, G.; Chatzigeorgiou, A.; Kalotychou, V.; Randeva, M.S.; Chatha, K.; et al. Empagliflozin Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE(-/-) Mice by Activating Autophagy and Reducing ER Stress and Apoptosis. Int. J. Mol. Sci. 2021, 22, 818. [Google Scholar] [CrossRef]
  126. Meng, Z.; Liu, X.; Li, T.; Fang, T.; Cheng, Y.; Han, L.; Sun, B.; Chen, L. The SGLT2 inhibitor empagliflozin negatively regulates IL-17/IL-23 axis-mediated inflammatory responses in T2DM with NAFLD via the AMPK/mTOR/autophagy pathway. Int. Immunopharmacol. 2021, 94, 107492. [Google Scholar] [CrossRef]
  127. Kucharewicz, I.; Pawlak, R.; Matys, T.; Pawlak, D.; Buczko, W. Antithrombotic effect of captopril and losartan is mediated by angiotensin-(1-7). Hypertension 2002, 40, 774–779. [Google Scholar] [CrossRef][Green Version]
  128. Ishiyama, Y.; Gallagher, P.E.; Averill, D.B.; Tallant, E.A.; Brosnihan, K.B.; Ferrario, C.M. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension 2004, 43, 970–976. [Google Scholar] [CrossRef][Green Version]
  129. Xu, Y.Z.; Zhang, X.; Wang, L.; Zhang, F.; Qiu, Q.; Liu, M.L.; Zhang, G.R.; Wu, X.L. An increased circulating angiotensin II concentration is associated with hypoadiponectinemia and postprandial hyperglycemia in men with nonalcoholic fatty liver disease. Intern. Med. 2013, 52, 855–861. [Google Scholar] [CrossRef][Green Version]
  130. Cao, X.; Yang, F.Y.; Xin, Z.; Xie, R.R.; Yang, J.K. The ACE2/Ang-(1-7)/Mas axis can inhibit hepatic insulin resistance. Mol. Cell. Endocrinol. 2014, 393, 30–38. [Google Scholar] [CrossRef]
  131. Nourjah, P.; Ahmad, S.R.; Karwoski, C.; Willy, M. Estimates of acetaminophen (Paracetomal)-associated overdoses in the United States. Pharmacoepidemiol. Drug Saf. 2006, 15, 398–405. [Google Scholar] [CrossRef] [PubMed]
  132. Lee, W.M. Etiologies of acute liver failure. Semin. Liver Dis. 2008, 28, 142–152. [Google Scholar] [CrossRef] [PubMed]
  133. McGreal, S.R.; Bhushan, B.; Walesky, C.; McGill, M.R.; Lebofsky, M.; Kandel, S.E.; Winefield, R.D.; Jaeschke, H.; Zachara, N.E.; Zhang, Z.; et al. Modulation of O-GlcNAc Levels in the Liver Impacts Acetaminophen-Induced Liver Injury by Affecting Protein Adduct Formation and Glutathione Synthesis. Toxicol. Sci. 2018, 162, 599–610. [Google Scholar] [CrossRef] [PubMed][Green Version]
  134. Filhoulaud, G.; Benhamed, F.; Pagesy, P.; Bonner, C.; Fardini, Y.; Ilias, A.; Movassat, J.; Burnol, A.F.; Guilmeau, S.; Kerr-Conte, J.; et al. O-GlcNacylation Links TxNIP to Inflammasome Activation in Pancreatic beta Cells. Front. Endocrinol. 2019, 10, 291. [Google Scholar] [CrossRef][Green Version]
  135. Hosseinpour-Arjmand, S.; Amirkhizi, F.; Ebrahimi-Mameghani, M. The effect of alpha-lipoic acid on inflammatory markers and body composition in obese patients with non-alcoholic fatty liver disease: A randomized, double-blind, placebo-controlled trial. J. Clin. Pharm. Ther. 2019, 44, 258–267. [Google Scholar] [CrossRef]
Figure 1. O-GlcNAcylation maintained normal physiological homeostasis in the liver. The HBP regulated the level of O-GlcNAcylation, and OGT catalyzed the transfer of single N-acetyl glucosamine from UDP-GlcNAC to the proteins; hydrolysis of a single N-acetylglucosamine from the proteins by OGA. O-GlcNAcylation of PGC-1α, FoxO1, and CRTC2 increases the expression of gluconeogenic genes and induces hepatic gluconeogenesis. O-GlcNAcylated p53 bound to the PCK1 promoter regulated the PCK1 levels and increased glucose synthesis. LXR, AMPK, ChREBP, and SREBP-1 were directly or indirectly regulated by O-GlcNAcylation, and subsequently, the transcriptional activity of target glycolysis and lipogenic genes was increased. HBP, hexosamine biosynthetic pathway; GFAT, glutamine fructose-6-phosphate amidotransferase; OGT, O-GlcNAc transferase; OGA, O-GlcNAcase; CRTC2, cAMP-regulated transcriptional co-activator 2; CREB, cyclic AMP-responsive element-binding protein; PGC1α, peroxisome proliferator-activated receptor-γ co-activator1α; ChREBP, carbohydrate-responsive element-binding protein; AMPK, AMP-activated protein kinase; SREBP-1, sterol regulatory element-binding protein 1; LXR, liver X receptors; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; SCD1, stearoyl-CoA desaturase1; MnSOD, manganese superoxide dismutase.
Figure 1. O-GlcNAcylation maintained normal physiological homeostasis in the liver. The HBP regulated the level of O-GlcNAcylation, and OGT catalyzed the transfer of single N-acetyl glucosamine from UDP-GlcNAC to the proteins; hydrolysis of a single N-acetylglucosamine from the proteins by OGA. O-GlcNAcylation of PGC-1α, FoxO1, and CRTC2 increases the expression of gluconeogenic genes and induces hepatic gluconeogenesis. O-GlcNAcylated p53 bound to the PCK1 promoter regulated the PCK1 levels and increased glucose synthesis. LXR, AMPK, ChREBP, and SREBP-1 were directly or indirectly regulated by O-GlcNAcylation, and subsequently, the transcriptional activity of target glycolysis and lipogenic genes was increased. HBP, hexosamine biosynthetic pathway; GFAT, glutamine fructose-6-phosphate amidotransferase; OGT, O-GlcNAc transferase; OGA, O-GlcNAcase; CRTC2, cAMP-regulated transcriptional co-activator 2; CREB, cyclic AMP-responsive element-binding protein; PGC1α, peroxisome proliferator-activated receptor-γ co-activator1α; ChREBP, carbohydrate-responsive element-binding protein; AMPK, AMP-activated protein kinase; SREBP-1, sterol regulatory element-binding protein 1; LXR, liver X receptors; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; SCD1, stearoyl-CoA desaturase1; MnSOD, manganese superoxide dismutase.
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Figure 2. O-GlcNAcylation attenuated insulin signaling. Normal insulin signaling (Left). Insulin binding to the insulin receptor (IR) leads to the recruitment of IRS-1 and activates PI3K, producing PIP3 and activating PDK1 and AKT. The PI3K/AKT pathway induces the expression of GLUT4 and its transport from intracellular vesicles to cell membranes to promote glucose uptake. In addition, the PI3K/AKT pathway activates GSK3β and GS to promote glycogen synthesis. Insulin signaling was inhibited by O-GlcNAcylation (Right). OGT inactivated key insulin signaling proteins, including IRS-1, PI3K, PDK1, AKT, and PTP1B, and attenuated insulin signaling and insulin resistance. PI3K, phosphatidylinositol-3-kinase; PDK1, phosphoinositide-dependent protein kinase 1; AKT, serine/threonine-protein kinase B; GSK3β, glycogen synthase kinase 3 beta; GS, glycogen synthase; PTP1B, protein tyrosine phosphatase 1B; OGT, O-GlcNAc transferase.
Figure 2. O-GlcNAcylation attenuated insulin signaling. Normal insulin signaling (Left). Insulin binding to the insulin receptor (IR) leads to the recruitment of IRS-1 and activates PI3K, producing PIP3 and activating PDK1 and AKT. The PI3K/AKT pathway induces the expression of GLUT4 and its transport from intracellular vesicles to cell membranes to promote glucose uptake. In addition, the PI3K/AKT pathway activates GSK3β and GS to promote glycogen synthesis. Insulin signaling was inhibited by O-GlcNAcylation (Right). OGT inactivated key insulin signaling proteins, including IRS-1, PI3K, PDK1, AKT, and PTP1B, and attenuated insulin signaling and insulin resistance. PI3K, phosphatidylinositol-3-kinase; PDK1, phosphoinositide-dependent protein kinase 1; AKT, serine/threonine-protein kinase B; GSK3β, glycogen synthase kinase 3 beta; GS, glycogen synthase; PTP1B, protein tyrosine phosphatase 1B; OGT, O-GlcNAc transferase.
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Figure 3. O-GlcNAcylation and NAFL-NASH-liver fibrosis-hepatoma tetralogy. The O-GlcNAcylation of the LXR, the ChREBP, and SREBP-1 promoted NAFL formation. O-GlcNAcylated NF-κB subunit p65 played a role in the progression of NASH by facilitating inflammatory damage, and the O-GlcNAcylated NF-κB subunit c-Rel exerted an anti-inflammatory effect. During liver fibrosis, O-GlcNAcylation of collagens accelerated fibrosis, while O-GlcNAcylation of the SRF represented anti-fibrotic effects. Finally, O-GlcNAcylated RIPK3 contributed to HCC. NAFL, non-alcoholic fatty liver; NASH, non-alcoholic steatohepatitis; LXR, Liver X receptor; carbohydrate-responsive element-binding protein; ChREBP, carbohydrate-responsive element-binding protein; SREBP-1, sterol regulatory element-binding protein 1; NF-κB, Nuclear factor-κB; SRF, serum response factor; HCC, hepatocellular carcinoma; OGT, O-GlcNAc transferase; GFAT, glutamine fructose-6-phosphate amidotransferase; ER stress, endoplasmic reticulum stress; HBP, hexosamine biosynthetic pathway; IRE1α, inositol requiring enzyme 1α; XBP1, X-box-binding protein 1; PDGFRβ, platelet-derived growth factor receptorβ; TFF2, trefoil factor 2; JNK, Jun N-terminal kinases.
Figure 3. O-GlcNAcylation and NAFL-NASH-liver fibrosis-hepatoma tetralogy. The O-GlcNAcylation of the LXR, the ChREBP, and SREBP-1 promoted NAFL formation. O-GlcNAcylated NF-κB subunit p65 played a role in the progression of NASH by facilitating inflammatory damage, and the O-GlcNAcylated NF-κB subunit c-Rel exerted an anti-inflammatory effect. During liver fibrosis, O-GlcNAcylation of collagens accelerated fibrosis, while O-GlcNAcylation of the SRF represented anti-fibrotic effects. Finally, O-GlcNAcylated RIPK3 contributed to HCC. NAFL, non-alcoholic fatty liver; NASH, non-alcoholic steatohepatitis; LXR, Liver X receptor; carbohydrate-responsive element-binding protein; ChREBP, carbohydrate-responsive element-binding protein; SREBP-1, sterol regulatory element-binding protein 1; NF-κB, Nuclear factor-κB; SRF, serum response factor; HCC, hepatocellular carcinoma; OGT, O-GlcNAc transferase; GFAT, glutamine fructose-6-phosphate amidotransferase; ER stress, endoplasmic reticulum stress; HBP, hexosamine biosynthetic pathway; IRE1α, inositol requiring enzyme 1α; XBP1, X-box-binding protein 1; PDGFRβ, platelet-derived growth factor receptorβ; TFF2, trefoil factor 2; JNK, Jun N-terminal kinases.
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Table 1. Role of O-GlcNAc on the process of NAFLD.
Table 1. Role of O-GlcNAc on the process of NAFLD.
Experiment TypeKey FactorDirectly Modified
or Not
Level of O-GlcNAcSpecific MechanismFinal ConclusionRef.
Animal and CellChREBPYesCells 11 03637 i001Cells 11 03637 i001 Transcriptional activity of L-PK, ACC, FAS, and SCD1Hepatic TG deposition[44]
Cell and AnimalSREBP-1NoCells 11 03637 i001Cells 11 03637 i001 SREBP-1 phosphorylation and stability via AMPK signalingTG deposition[43]
Cell and AnimalIP6K1NoCells 11 03637 i001UnclarifiedPromote NASH and fibrosis[17]
Cell and AnimalNF-κBYesCells 11 03637 i001p65 is modified to induce activation of NFκBInflammatory damage[60]
c-Rel is modified and activatedAnti-inflammatory effect[61]
CellCollagenYesCells 11 03637 i001Activate HSCsLiver fibrosis[62]
Animal & CellSRFYesCells 11 03637 i001Inhibited SRF activity to induce α-SMA transcriptionPrevent liver fibrosis[63]
Animal & CellRIPK3YesCells 11 03637 i001Cells 11 03637 i002 RIPK3 stability, caspase 8 cleavage, and JNK activationPromote NAFLD-HCC[64,65]
ChREBP, carbohydrate-responsive element-binding protein; L-PK, liver pyruvate kinase; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; SCD1, stearoyl-CoA desaturase1; TG, thyroglobulin; SREBP-1, sterol regulatory element-binding protein 1; AMPK, AMP-activated protein kinase; IP6K1, inositol hexakisphosphate kinases 1; NASH, non-alcoholic steatohepatitis; NF-κB, Nuclear factor-κB; HSCs, hepatic stellate cells; SRF, serum response factor; α-SMA, α-smooth muscle actin; RIPK3, receptor-interacting protein kinase 3; JNK, c-Jun N-terminal kinases; NAFLD-HCC, NAFLD-associated hepatocellular carcinoma. Up arrow represents up-regulation, Down arrow represents down-regulation.
Table 2. Drug interactions with O-GlcNAcylation and NAFLD.
Table 2. Drug interactions with O-GlcNAcylation and NAFLD.
Drug.Correlation with O-GlcNAcylationEffects on NAFLDRef.
METCells 11 03637 i002 O-GlcNAcylation of AMP, NF-κB, and ChREBPCells 11 03637 i002 Liver TG accumulation and improved NAFLD[97,98,99,101]
GLP-1O-GlcNAcylation enhance GLP-1 activityCells 11 03637 i002 Liver enzyme levels and liver fat[102,103]
SGLT-2IReduced O-GlcNAcylation exerts an anti-fibrotic effectCells 11 03637 i001 Liver steatosis and liver fibrosis[104,105]
ACEIEnhancement of Ang1-7 axis to reduce O-GlcNAcylationCells 11 03637 i002 Incidence of liver cancer and cirrhosis[106,107]
GSHPositive correlation between c-Jun O-GlcNAcylation and GSH synthesissupported liver metabolism and improved NAFLD[108,109]
ALACells 11 03637 i002 O-GlcNAcylation of ERK, p38, CuZnSOD, CAT, HSP70, and HSP90Cells 11 03637 i002 Liver TG accumulation and improved NAFLD[110,111,112,113]
CurcuminInhibition O-GlcNAcylation and blocked NF-κB signaling pathwayExert anti-inflammatory effect, alleviated NAFLD/NASH[19]
SilibininInhibition of O-GlcNAcylation and blocked NF-κB signaling pathwayAnti-inflammatory effect, alleviated NASH[18]
NAFLD, non-alcoholic fatty liver disease; MET, metformin; AMP, cyclic adenosine monophosphate; NF-κB, Nuclear factor-κB; ChREBP, carbohydrate-responsive element-binding protein; GLP-1, glucagon-like peptide-1; SGLT-2I, sodium-glucose cotransporter 2 inhibitor; Ang, angiotensin; ACEI, Ang converting enzyme inhibitors; GSH, glutathione; ALA, alpha-lipoic acid; CuZnSOD, CuZn-superoxide dismutase; CAT, catalase; HSP, heat shock proteins. Up arrow represents up-regulation, Down arrow represents down-regulation.
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Zhou, Y.; Li, Z.; Xu, M.; Zhang, D.; Ling, J.; Yu, P.; Shen, Y. O-GlycNacylation Remission Retards the Progression of Non-Alcoholic Fatty Liver Disease. Cells 2022, 11, 3637.

AMA Style

Zhou Y, Li Z, Xu M, Zhang D, Ling J, Yu P, Shen Y. O-GlycNacylation Remission Retards the Progression of Non-Alcoholic Fatty Liver Disease. Cells. 2022; 11(22):3637.

Chicago/Turabian Style

Zhou, Yicheng, Zhangwang Li, Minxuan Xu, Deju Zhang, Jitao Ling, Peng Yu, and Yunfeng Shen. 2022. "O-GlycNacylation Remission Retards the Progression of Non-Alcoholic Fatty Liver Disease" Cells 11, no. 22: 3637.

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