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20 pages, 9409 KiB

Open AccessArticle

Polysaccharide from Salviae miltiorrhizae Radix et Rhizoma Attenuates the Progress of Obesity-Induced Non-Alcoholic Fatty Liver Disease through Modulating Intestinal Microbiota-Related Gut–Liver Axis

by Lixia Li, Xinting Lan, Xi Peng, Shuai Shi, Yanlin Zhao, Wentao Liu, Qihui Luo, Lanlan Jia, Bin Feng, Zhengli Chen, Yuanfeng Zou and Chao Huang

Int. J. Mol. Sci. 2022, 23(18), 10620; https://doi.org/10.3390/ijms231810620 - 13 Sep 2022

Cited by 9 | Viewed by 2992

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide, thus treatments for it have attracted lots of interest. In this study, the Salviae miltiorrhizae Radix et Rhizoma (SMRR) polysaccharide was isolated by hot water extraction and ethanol precipitation, and [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide, thus treatments for it have attracted lots of interest. In this study, the Salviae miltiorrhizae Radix et Rhizoma (SMRR) polysaccharide was isolated by hot water extraction and ethanol precipitation, and then purified by DEAE anion exchange chromatography and gel filtration. With a high-fat-diet-induced obesity/NAFLD mouse model, we found that consumption of the SMRR polysaccharide could remarkably reverse obesity and its related progress of NAFLD, including attenuated hepatocellular steatosis, hepatic fibrosis and inflammation. In addition, we also reveal the potential mechanism behind these is that the SMRR polysaccharide could regulate the gut–liver axis by modulating the homeostasis of gut microbiota and thereby improving intestinal function. Full article

(This article belongs to the Special Issue Molecular Advances in MAFLD)

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16 pages, 5568 KiB

Open AccessArticle

Loss of TRIM67 Attenuates the Progress of Obesity-Induced Non-Alcoholic Fatty Liver Disease

by Chao Huang, Xiaoli Wei, Qihui Luo, Yu Xia, Ting Pan, Junbo He, Asad Jahangir, Lanlan Jia, Wentao Liu, Yuanfeng Zou, Lixia Li, Hongrui Guo, Yi Geng and Zhengli Chen

Int. J. Mol. Sci. 2022, 23(13), 7475; https://doi.org/10.3390/ijms23137475 - 05 Jul 2022

Cited by 10 | Viewed by 2439

Abstract

Obesity is considered as a major cause for the development and progress of non-alcoholic fatty liver disease (NAFLD), which is one of the most prevalent chronic liver diseases worldwide. However, molecular mechanisms that implicate in obesity-driven pathophysiology of NAFLD are not well defined. [...] Read more.

Obesity is considered as a major cause for the development and progress of non-alcoholic fatty liver disease (NAFLD), which is one of the most prevalent chronic liver diseases worldwide. However, molecular mechanisms that implicate in obesity-driven pathophysiology of NAFLD are not well defined. Here, we report a tripartite motif (TRIM) protein family member—TRIM67—that is hardly expressed in liver but is inducible on obese conditions. Enhanced expression of TRIM67 activates hepatic inflammation to disturb lipid metabolic homeostasis and promote the progress of NAFLD induced by obesity, while the deficiency in TRIM67 is protective against these pathophysiological processes. Finally, we show that the important transcription coactivator PGC-1α implicates in the response of hepatic TRIM67 to obesity. Full article

(This article belongs to the Special Issue Molecular Advances in MAFLD)

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17 pages, 1467 KiB

Open AccessArticle

Genetic Deficiency of Indoleamine 2,3-dioxygenase Aggravates Vascular but Not Liver Disease in a Nonalcoholic Steatohepatitis and Atherosclerosis Comorbidity Model

by Aastha Arora, Gustavo Luis Tripodi, Ilona Kareinen, Martin Berg, Maria Josefa Forteza, Anton Gisterå, Silke Griepke, Felipe Beccaria Casagrande, Joilson O. Martins, Dulcineia Saes Parra Abdalla, Jennifer Cole, Claudia Monaco and Daniel F. J. Ketelhuth

Int. J. Mol. Sci. 2022, 23(9), 5203; https://doi.org/10.3390/ijms23095203 - 06 May 2022

Cited by 3 | Viewed by 2951

Abstract

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that increases cardiovascular disease risk. Indoleamine 2,3-dioxygenase-1 (IDO1)-mediated tryptophan (Trp) metabolism has been proposed to play an immunomodulatory role in several diseases. The potential of IDO1 to be a link between NASH and cardiovascular disease [...] Read more.

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that increases cardiovascular disease risk. Indoleamine 2,3-dioxygenase-1 (IDO1)-mediated tryptophan (Trp) metabolism has been proposed to play an immunomodulatory role in several diseases. The potential of IDO1 to be a link between NASH and cardiovascular disease has never been investigated. Using Apoe^−/−and Apoe^−/−Ido1^−/− mice that were fed a high-fat, high-cholesterol diet (HFCD) to simultaneously induce NASH and atherosclerosis, we found that Ido1 deficiency significantly accelerated atherosclerosis after 7 weeks. Surprisingly, Apoe^−/−Ido1^−/− mice did not present a more aggressive NASH phenotype, including hepatic lipid deposition, release of liver enzymes, and histopathological parameters. As expected, a lower L-kynurenine/Trp (Kyn/Trp) ratio was found in the plasma and arteries of Apoe^−/−Ido1^−/− mice compared to controls. However, no difference in the hepatic Kyn/Trp ratio was found between the groups. Hepatic transcript analyses revealed that HFCD induced a temporal increase in tryptophan 2,3-dioxygenase (Tdo2) mRNA, indicating an alternative manner to maintain Trp degradation during NASH development in both Apoe^−/− and Apoe^−/−Ido1^−/mice⁻. Using HepG2 hepatoma cell and THP1 macrophage cultures, we found that iron, TDO2, and Trp degradation may act as important mediators of cross-communication between hepatocytes and macrophages regulating liver inflammation. In conclusion, we show that Ido1 deficiency aggravates atherosclerosis, but not liver disease, in a newly established NASH and atherosclerosis comorbidity model. Our data indicate that the overexpression of TDO2 is an important mechanism that helps in balancing the kynurenine pathway and inflammation in the liver, but not in the artery wall, which likely determined disease outcome in these two target tissues. Full article

(This article belongs to the Special Issue Molecular Advances in MAFLD)

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Review

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52 pages, 2019 KiB

Open AccessReview

Lessons on Drug Development: A Literature Review of Challenges Faced in Nonalcoholic Fatty Liver Disease (NAFLD) Clinical Trials

by Joel Yeh Siang Chen, Damien Chua, Carissa Odelia Lim, Wan Xi Ho and Nguan Soon Tan

Int. J. Mol. Sci. 2023, 24(1), 158; https://doi.org/10.3390/ijms24010158 - 21 Dec 2022

Cited by 6 | Viewed by 3991

Abstract

NAFLD is the most common chronic liver disease worldwide, occurring in both obese and lean patients. It can lead to life-threatening liver diseases and nonhepatic complications, such as cirrhosis and cardiovascular diseases, that burden public health and the health care system. Current care [...] Read more.

NAFLD is the most common chronic liver disease worldwide, occurring in both obese and lean patients. It can lead to life-threatening liver diseases and nonhepatic complications, such as cirrhosis and cardiovascular diseases, that burden public health and the health care system. Current care is weight loss through diet and exercise, which is a challenging goal to achieve. However, there are no FDA-approved pharmacotherapies for NAFLD. This review thoroughly examines the clinical trial findings from 22 drugs (Phase 2 and above) and evaluates the future direction that trials should take for further drug development. These trialed drugs can broadly be categorized into five groups—hypoglycemic, lipid-lowering, bile-pathway, anti-inflammatory, and others, which include nutraceuticals. The multitude of challenges faced in these yet-to-be-approved NAFLD drug trials provided insight into a few areas of improvement worth considering. These include drug repurposing, combinations, noninvasive outcomes, standardization, adverse event alleviation, and the need for precision medicine with more extensive consideration of NAFLD heterogenicity in drug trials. Understandably, every evolution of the drug development landscape lies with its own set of challenges. However, this paper believes in the importance of always learning from lessons of the past, with each potential improvement pushing clinical trials an additional step forward toward discovering appropriate drugs for effective NAFLD management. Full article

(This article belongs to the Special Issue Molecular Advances in MAFLD)

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47 pages, 2954 KiB

Open AccessReview

Utility of Human Relevant Preclinical Animal Models in Navigating NAFLD to MAFLD Paradigm

by Damien Chua, Zun Siong Low, Guo Xiang Cheam, Aik Seng Ng and Nguan Soon Tan

Int. J. Mol. Sci. 2022, 23(23), 14762; https://doi.org/10.3390/ijms232314762 - 25 Nov 2022

Cited by 4 | Viewed by 2963

Abstract

Fatty liver disease is an emerging contributor to disease burden worldwide. The past decades of work established the heterogeneous nature of non-alcoholic fatty liver disease (NAFLD) etiology and systemic contributions to the pathogenesis of the disease. This called for the proposal of a [...] Read more.

Fatty liver disease is an emerging contributor to disease burden worldwide. The past decades of work established the heterogeneous nature of non-alcoholic fatty liver disease (NAFLD) etiology and systemic contributions to the pathogenesis of the disease. This called for the proposal of a redefinition in 2020 to that of metabolic dysfunction-associated fatty liver disease (MAFLD) to better reflect the current understanding of the disease. To date, several clinical cohort studies comparing NAFLD and MAFLD hint at the relevancy of the new nomenclature in enriching for patients with more severe hepatic injury and extrahepatic comorbidities. However, the underlying systemic pathogenesis is still not fully understood. Preclinical animal models have been imperative in elucidating key biological mechanisms in various contexts, including intrahepatic disease progression, interorgan crosstalk and systemic dysregulation. Furthermore, they are integral in developing novel therapeutics against MAFLD. However, substantial contextual variabilities exist across different models due to the lack of standardization in several aspects. As such, it is crucial to understand the strengths and weaknesses of existing models to better align them to the human condition. In this review, we consolidate the implications arising from the change in nomenclature and summarize MAFLD pathogenesis. Subsequently, we provide an updated evaluation of existing MAFLD preclinical models in alignment with the new definitions and perspectives to improve their translational relevance. Full article

(This article belongs to the Special Issue Molecular Advances in MAFLD)

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28 pages, 1939 KiB

Open AccessReview

Advancements in MAFLD Modeling with Human Cell and Organoid Models

by Shi-Xiang Wang, Ji-Song Yan and Yun-Shen Chan

Int. J. Mol. Sci. 2022, 23(19), 11850; https://doi.org/10.3390/ijms231911850 - 06 Oct 2022

Cited by 7 | Viewed by 3050

Abstract

Metabolic (dysfunction) associated fatty liver disease (MAFLD) is one of the most prevalent liver diseases and has no approved therapeutics. The high failure rates witnessed in late-phase MAFLD drug trials reflect the complexity of the disease, and how the disease develops and progresses [...] Read more.

Metabolic (dysfunction) associated fatty liver disease (MAFLD) is one of the most prevalent liver diseases and has no approved therapeutics. The high failure rates witnessed in late-phase MAFLD drug trials reflect the complexity of the disease, and how the disease develops and progresses remains to be fully understood. In vitro, human disease models play a pivotal role in mechanistic studies to unravel novel disease drivers and in drug testing studies to evaluate human-specific responses. This review focuses on MAFLD disease modeling using human cell and organoid models. The spectrum of patient-derived primary cells and immortalized cell lines employed to model various liver parenchymal and non-parenchymal cell types essential for MAFLD development and progression is discussed. Diverse forms of cell culture platforms utilized to recapitulate tissue-level pathophysiology in different stages of the disease are also reviewed. Full article

(This article belongs to the Special Issue Molecular Advances in MAFLD)

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18 pages, 1052 KiB

Open AccessReview

Molecular Advances in MAFLD—A Link between Sphingolipids and Extracellular Matrix in Development and Progression to Fibrosis

by Adrian Kołakowski, Sylwia Dziemitko, Aleksandra Chmielecka, Hubert Żywno, Wiktor Bzdęga, Tomasz Charytoniuk, Adrian Chabowski and Karolina Konstantynowicz-Nowicka

Int. J. Mol. Sci. 2022, 23(19), 11380; https://doi.org/10.3390/ijms231911380 - 27 Sep 2022

Cited by 2 | Viewed by 2146

Abstract

Metabolic-Associated Fatty Liver Disease (MAFLD) is a major cause of liver diseases globally and its prevalence is expected to grow in the coming decades. The main cause of MAFLD development is changed in the composition of the extracellular matrix (ECM). Increased production of [...] Read more.

Metabolic-Associated Fatty Liver Disease (MAFLD) is a major cause of liver diseases globally and its prevalence is expected to grow in the coming decades. The main cause of MAFLD development is changed in the composition of the extracellular matrix (ECM). Increased production of matrix molecules and inflammatory processes lead to progressive fibrosis, cirrhosis, and ultimately liver failure. In addition, increased accumulation of sphingolipids accompanied by increased expression of pro-inflammatory cytokines in the ECM is closely related to lipogenesis, MAFLD development, and its progression to fibrosis. In our work, we will summarize all information regarding the role of sphingolipids e.g., ceramide and S1P in MAFLD development. These sphingolipids seem to have the most significant effect on macrophages and, consequently, HSCs which trigger the entire cascade of overproduction matrix molecules, especially type I and III collagen, proteoglycans, elastin, and also tissue inhibitors of metalloproteinases, which as a result cause the development of liver fibrosis. Full article

(This article belongs to the Special Issue Molecular Advances in MAFLD)

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18 pages, 1104 KiB

Open AccessReview

Autophagy Dysregulation in Metabolic Associated Fatty Liver Disease: A New Therapeutic Target

by Chun-Liang Chen and Yu-Cheng Lin

Int. J. Mol. Sci. 2022, 23(17), 10055; https://doi.org/10.3390/ijms231710055 - 02 Sep 2022

Cited by 14 | Viewed by 4513

Abstract

Metabolic associated fatty liver disease (MAFLD) is one of the most common causes of chronic liver disease worldwide. To date, there is no FDA-approved treatment, so there is an urgent need to determine its pathophysiology and underlying molecular mechanisms. Autophagy is a lysosomal [...] Read more.

Metabolic associated fatty liver disease (MAFLD) is one of the most common causes of chronic liver disease worldwide. To date, there is no FDA-approved treatment, so there is an urgent need to determine its pathophysiology and underlying molecular mechanisms. Autophagy is a lysosomal degradation pathway that removes damaged organelles and misfolded proteins after cell injury through endoplasmic reticulum stress or starvation, which inhibits apoptosis and promotes cell survival. Recent studies have shown that autophagy plays an important role in removing lipid droplets from hepatocytes. Autophagy has also been reported to inhibit the production of pro-inflammatory cytokines and provide energy for the hepatic stellate cells activation during liver fibrosis. Thyroid hormone, irisin, melatonin, hydrogen sulfide, sulforaphane, DA-1241, vacuole membrane protein 1, nuclear factor erythroid 2-related factor 2, sodium-glucose co-transporter type-2 inhibitors, immunity-related GTPase M, and autophagy-related gene 7 have been reported to ameliorate MAFLD via autophagic induction. Lipid receptor CD36, SARS-CoV-2 Spike protein and leucine aminopeptidase 3 play a negative role in the autophagic function. This review summarizes recent advances in the role of autophagy in MAFLD. Autophagy modulates major pathological changes, including hepatic lipid metabolism, inflammation, and fibrosis, suggesting the potential of modulating autophagy for the treatment of MAFLD. Full article

(This article belongs to the Special Issue Molecular Advances in MAFLD)

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