Molecular and Cellular Mechanisms of Diseases: Liver Diseases

Topic Information

Dear Colleagues,

In 1986, Prof. Jay Hoofnagle was not yet the Digestive Diseases and Nutrition Division Director at the NIDDK, NIH. However, he had already published his pioneering work on Hepatitis B interferon treatment. In December 1986, his seminal article on treatment with recombinant human alpha interferon of what was called chronic non-A non-B hepatitis—and later became HCV hepatitis—opened a new era not only for the future of hepatitis C but for the entire field of hepatology. Until then, hepatitis C has been believed untreatable, the natural history of all viral hepatitis had not been completely elucidated, and diagnostic assays for hepatitis B and C had not been discovered. The availability of antiviral treatment for chronic hepatitis attracted interest in liver diseases, and the eventual approval of interferon for hepatitis B and C treatment was the driver for supporting research in the field. What are the remaining issues in hepatology after that exciting period? Some of the remaining challenges researchers in liver diseases are working on are how treatment now based on oral direct-acting antivirals impact the outcomes of HCV hepatitis; when the experimental compounds for hepatitis B and delta treatment will become available, and how they will be used; whether the diagnostics of HBV-related diseases will now change and how the efforts in reaching underserved populations at high risk for HCV infection transmission, such as the homeless and people injecting drugs, will succeed. This Topic will collect a series of essays addressing aspects of liver diseases’ pathogenesis and treatment, including the most recent advances in DILI and actions to promote liver disease research, training, and education, as well as changes in the field of liver diseases across the world.

Prof. Dr. Alessandra Mangia
Prof. Dr. Maria Guido
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomolecules biomolecules	5.5	8.3	2011	16.9 Days	CHF 2700
Cells cells	6.0	9.0	2012	16.6 Days	CHF 2700
International Journal of Molecular Sciences ijms	5.6	7.8	2000	16.3 Days	CHF 2900
Journal of Clinical Medicine jcm	3.9	5.4	2012	17.9 Days	CHF 2600
Journal of Molecular Pathology jmp	-	-	2020	24.9 Days	CHF 1000

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Published Papers (12 papers)

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16 pages, 1373 KiB  

Open AccessReview

Mechanisms of Inflammasome Activation and Involvement in Liver Disease

by Ananda Baral

J. Mol. Pathol. 2024, 5(2), 171-186; https://doi.org/10.3390/jmp5020011 - 13 Apr 2024

Viewed by 292

Abstract

The liver is a multi-potent organ with important metabolic, immunological and endocrine functions. Hepatic physiology is maintained at a balanced state via the delicate actions of different liver-resident cells. Among several factors that modulate hepatic physiology, the harmony between the activity of pro- [...] Read more.

The liver is a multi-potent organ with important metabolic, immunological and endocrine functions. Hepatic physiology is maintained at a balanced state via the delicate actions of different liver-resident cells. Among several factors that modulate hepatic physiology, the harmony between the activity of pro- and anti-inflammatory cytokines is a crucial determinant. However, initiation of inflammatory activity can be detrimental if it goes unresolved, leading to severe consequences such as hepatitis, hepatic fibrosis, cirrhosis or even hepatocellular carcinoma (HCC). Different physiological processes can modulate the hepatic microenvironment; one such factor is a cytosolic protein complex called the inflammasome. Inflammasome activation is a consequence of the cellular encounter with pathogens or products of cellular damage. Once activated, inflammasomes promote the maturation of interleukin-1 family cytokines such as IL-1β and IL-18 via activation of caspase-1. These cytokines have a very potent role in modulating hepatic physiology. Various lines of reports suggest that inflammasome activation and IL-1 cytokines play critical roles in liver diseases, including hepatitis, hepatic fibrosis and HCC. Conversely, inhibition of inflammasome activation and/or IL-1 signaling prevents such effects. This review summarizes the mechanisms leading to inflammasome activation and the role it plays in hepatic physiology. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Liver Diseases)

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14 pages, 4968 KiB  

Open AccessArticle

Gut Microbiota Metabolite 3-Indolepropionic Acid Directly Activates Hepatic Stellate Cells by ROS/JNK/p38 Signaling Pathways

by Xiaoyan Yuan, Junting Yang, Yuling Huang, Jia Li and Yuanyuan Li

Biomolecules 2023, 13(10), 1464; https://doi.org/10.3390/biom13101464 - 28 Sep 2023

Cited by 1 | Viewed by 1336

Abstract

There has been a growing interest in studying the communication of gut microbial metabolites between the gut and the liver as liver fibrosis progresses. Although 3-Indolepropionic acid (IPA) is regarded as a clinically valuable gut metabolite for the treatment of certain chronic diseases, [...] Read more.

There has been a growing interest in studying the communication of gut microbial metabolites between the gut and the liver as liver fibrosis progresses. Although 3-Indolepropionic acid (IPA) is regarded as a clinically valuable gut metabolite for the treatment of certain chronic diseases, the effects of oral administration of IPA on hepatic fibrosis in different animal models have been conflicting. While some mechanisms have been proposed to explain these contradictory effects, the direct impact of IPA on hepatic fibrosis remains unclear. In this study, we found that IPA could directly activate LX-2 human hepatic stellate cells in vitro. IPA upregulated the expression of fibrogenic marker genes and promoted the features associated with HSCs activation, including proliferation and contractility. IPA also increased reactive oxygen species (ROS) in mitochondria and the expression of inflammation-related genes in LX-2 cells. However, when a ROS-blocking agent was used, these effects were reduced. p38 and JNK, the downstream signaling cascades of ROS, were found to be required for the activation of LX-2 induced by IPA. These findings suggest that IPA can directly activate hepatic stellate cells through ROS-induced JNK and p38 signaling pathways. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Liver Diseases)

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19 pages, 870 KiB  

Open AccessReview

Unfolded Protein Response Signaling in Liver Disorders: A 2023 Updated Review

by Smriti Shreya, Christophe F. Grosset and Buddhi Prakash Jain

Int. J. Mol. Sci. 2023, 24(18), 14066; https://doi.org/10.3390/ijms241814066 - 14 Sep 2023

Cited by 3 | Viewed by 1565

Abstract

Endoplasmic reticulum (ER) is the site for synthesis and folding of secreted and transmembrane proteins. Disturbance in the functioning of ER leads to the accumulation of unfolded and misfolded proteins, which finally activate the unfolded protein response (UPR) signaling. The three branches of [...] Read more.

Endoplasmic reticulum (ER) is the site for synthesis and folding of secreted and transmembrane proteins. Disturbance in the functioning of ER leads to the accumulation of unfolded and misfolded proteins, which finally activate the unfolded protein response (UPR) signaling. The three branches of UPR—IRE1 (Inositol requiring enzyme 1), PERK (Protein kinase RNA-activated (PKR)-like ER kinase), and ATF6 (Activating transcription factor 6)—modulate the gene expression pattern through increased expression of chaperones and restore ER homeostasis by enhancing ER protein folding capacity. The liver is a central organ which performs a variety of functions which help in maintaining the overall well-being of our body. The liver plays many roles in cellular physiology, blood homeostasis, and detoxification, and is the main site at which protein synthesis occurs. Disturbance in ER homeostasis is triggered by calcium level imbalance, change in redox status, viral infection, and so on. ER dysfunction and subsequent UPR signaling participate in various hepatic disorders like metabolic (dysfunction) associated fatty liver disease, liver cancer, viral hepatitis, and cholestasis. The exact role of ER stress and UPR signaling in various liver diseases is not fully understood and needs further investigation. Targeting UPR signaling with drugs is the subject of intensive research for therapeutic use in liver diseases. The present review summarizes the role of UPR signaling in liver disorders and describes why UPR regulators are promising therapeutic targets. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Liver Diseases)

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20 pages, 4151 KiB  

Open AccessArticle

Targeted MicroRNA Profiling Reveals That Exendin-4 Modulates the Expression of Several MicroRNAs to Reduce Steatosis in HepG2 Cells

by Olfa Khalifa, Khalid Ouararhni, Khaoula Errafii, Nehad M. Alajez and Abdelilah Arredouani

Int. J. Mol. Sci. 2023, 24(14), 11606; https://doi.org/10.3390/ijms241411606 - 18 Jul 2023

Cited by 1 | Viewed by 1380

Abstract

Excess hepatic lipid accumulation is the hallmark of non-alcoholic fatty liver disease (NAFLD), for which no medication is currently approved. However, glucagon-like peptide-1 receptor agonists (GLP-1RAs), already approved for treating type 2 diabetes, have lately emerged as possible treatments. Herein we aim to [...] Read more.

Excess hepatic lipid accumulation is the hallmark of non-alcoholic fatty liver disease (NAFLD), for which no medication is currently approved. However, glucagon-like peptide-1 receptor agonists (GLP-1RAs), already approved for treating type 2 diabetes, have lately emerged as possible treatments. Herein we aim to investigate how the GLP-1RA exendin-4 (Ex-4) affects the microRNA (miRNAs) expression profile using an in vitro model of steatosis. Total RNA, including miRNAs, was isolated from control, steatotic, and Ex-4-treated steatotic cells and used for probing a panel of 799 highly curated miRNAs using NanoString technology. Enrichment pathway analysis was used to find the signaling pathways and cellular functions associated with the differentially expressed miRNAs. Our data shows that Ex-4 reversed the expression of a set of miRNAs. Functional enrichment analysis highlighted many relevant signaling pathways and cellular functions enriched in the differentially expressed miRNAs, including hepatic fibrosis, insulin receptor, PPAR, Wnt/β-Catenin, VEGF, and mTOR receptor signaling pathways, fibrosis of the liver, cirrhosis of the liver, proliferation of hepatic stellate cells, diabetes mellitus, glucose metabolism disorder and proliferation of liver cells. Our findings suggest that miRNAs may play essential roles in the processes driving steatosis reduction in response to GLP-1R agonists, which warrants further functional investigation. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Liver Diseases)

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12 pages, 3403 KiB  

Open AccessArticle

Acetyl-L-Carnitine and Liposomal Co-Enzyme Q₁₀ Attenuate Hepatic Inflammation, Apoptosis, and Fibrosis Induced by Propionic Acid

by Ahlam M. Alhusaini, Rahaf Alsoghayer, Lina Alhushan, Abeer M. Alanazi and Iman H. Hasan

Int. J. Mol. Sci. 2023, 24(14), 11519; https://doi.org/10.3390/ijms241411519 - 15 Jul 2023

Cited by 2 | Viewed by 1400

Abstract

Propionic acid (PRA) is a metabolic end-product of enteric bacteria in the gut, and it is commonly used as a food preservative. Despite the necessity of PRA for immunity in the body, excessive exposure to this product may result in disruptive effects. The [...] Read more.

Propionic acid (PRA) is a metabolic end-product of enteric bacteria in the gut, and it is commonly used as a food preservative. Despite the necessity of PRA for immunity in the body, excessive exposure to this product may result in disruptive effects. The purpose of this study is to examine the hepatoprotective effects of acetyl-L-carnitine (A-CAR) and liposomal-coenzyme Q₁₀ (L-CoQ₁₀) against PRA-induced injury. Liver injury in rats was induced by oral administration of PRA, and A-CAR and L-CoQ₁₀ were administered concurrently with PRA for 5 days. Oxidative stress, inflammatory, apoptotic, and fibrotic biomarkers were analyzed; the histology of liver tissue was assessed as well to further explore any pathological alterations. PRA caused significant increases in the levels of serum liver enzymes and hepatic oxidative stress, inflammatory, and apoptotic biomarker levels, along with histopathological alterations. Concurrent treatment with A-CAR and/or L-CoQ₁₀ with PRA prevented tissue injury and decreased the levels of oxidative stress, proinflammatory cytokines, and apoptotic markers. Additionally, A-CAR and/or L-CoQ₁₀ modulated the expression of high-mobility group box-1, cytokeratin-18, transforming growth factor-beta1, and SMAD3 in liver tissue. In conclusion, A-CAR and/or L-CoQ₁₀ showed hepatoprotective efficacy by reducing oxidative stress, the inflammatory response, apoptosis, and fibrosis in liver tissue. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Liver Diseases)

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22 pages, 4566 KiB  

Open AccessArticle

The Influence of Single Nucleotide Polymorphisms on Vitamin D Receptor Protein Levels and Function in Chronic Liver Disease

by Evanthia Tourkochristou, Efthymios P. Tsounis, Haralampos Tzoupis, Ioanna Aggeletopoulou, Aggeliki Tsintoni, Theoni Lourida, Georgia Diamantopoulou, Konstantinos Zisimopoulos, Theodora Kafentzi, Anne-Lise de Lastic, Maria Rodi, Theodore Tselios, Konstantinos Thomopoulos, Athanasia Mouzaki and Christos Triantos

Int. J. Mol. Sci. 2023, 24(14), 11404; https://doi.org/10.3390/ijms241411404 - 13 Jul 2023

Viewed by 1608

Abstract

Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene have been associated with chronic liver disease. We investigated the role of VDR SNPs on VDR protein levels and function in patients with chronic liver disease. VDR expression levels were determined in [...] Read more.

Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene have been associated with chronic liver disease. We investigated the role of VDR SNPs on VDR protein levels and function in patients with chronic liver disease. VDR expression levels were determined in peripheral T lymphocytes (CD3+VDR+), monocytes (CD14+VDR+), and plasma from patients (n = 66) and healthy controls (n = 38). Genotyping of SNPs and the determination of expression of VDR/vitamin D-related genes were performed by using qPCR. The effect of FokI SNP on vitamin D-binding to VDR was investigated by molecular dynamics simulations. CD14+VDR+ cells were correlated with the MELD score. The ApaI SNP was associated with decreased CD3+VDR+ levels in cirrhotic patients and with higher liver stiffness in HCV patients. The BsmI and TaqI SNPs were associated with increased VDR plasma concentrations in cirrhotic patients and decreased CD14+VDR+ levels in HCV patients. The FokI SNP was associated with increased CD3+VDR+ levels in cirrhotic patients and controls. VDR polymorphisms were significantly related to the expression of genes critical for normal hepatocyte function and immune homeostasis. VDR expression levels were related to the clinical severity of liver disease. VDR SNPs may be related to the progression of chronic liver disease by affecting VDR expression levels. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Liver Diseases)

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20 pages, 893 KiB  

Open AccessReview

Overview of CircRNAs Roles and Mechanisms in Liver Fibrosis

by Gaiping Wang, Jiahui Tong, Yingle Li, Xianglei Qiu, Anqi Chen, Cuifang Chang and Guoying Yu

Biomolecules 2023, 13(6), 940; https://doi.org/10.3390/biom13060940 - 05 Jun 2023

Viewed by 1503

Abstract

Liver fibrosis represents the reversible pathological process with the feature of the over-accumulation of extracellular matrix (ECM) proteins within the liver, which results in the deposition of fibrotic tissues and liver dysfunction. Circular noncoding RNAs (CircRNAs) have the characteristic closed loop structures, which [...] Read more.

Liver fibrosis represents the reversible pathological process with the feature of the over-accumulation of extracellular matrix (ECM) proteins within the liver, which results in the deposition of fibrotic tissues and liver dysfunction. Circular noncoding RNAs (CircRNAs) have the characteristic closed loop structures, which show high resistance to exonuclease RNase, making them far more stable and recalcitrant against degradation. CircRNAs increase target gene levels by playing the role of a microRNA (miRNA) sponge. Further, they combine with proteins or play the role of RNA scaffolds or translate proteins to modulate different biological processes. Recent studies have indicated that CircRNAs play an important role in the occurrence and progression of liver fibrosis and may be the potential diagnostic and prognostic markers for liver fibrosis. This review summarizes the CircRNAs roles and explores their underlying mechanisms, with a special focus on some of the latest research into key CircRNAs related to regulating liver fibrosis. Results in this work may inspire fruitful research directions and applications of CircRNAs in the management of liver fibrosis. Additionally, our findings lay a critical theoretical foundation for applying CircRNAs in diagnosing and treating liver fibrosis. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Liver Diseases)

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17 pages, 5226 KiB  

Open AccessArticle

Myeloid Trem2 Dynamically Regulates the Induction and Resolution of Hepatic Ischemia-Reperfusion Injury Inflammation

by Sheng Han, Xiangdong Li, Nan Xia, Yu Zhang, Wenjie Yu, Jie Li, Chenyu Jiao, Ziyi Wang and Liyong Pu

Int. J. Mol. Sci. 2023, 24(7), 6348; https://doi.org/10.3390/ijms24076348 - 28 Mar 2023

Cited by 2 | Viewed by 2092

Abstract

Trem2, a transmembrane protein that is simultaneously expressed in both bone marrow-derived and embryonic-derived liver-resident macrophages, plays a complex role in liver inflammation. The unique role of myeloid Trem2 in hepatic ischemia-reperfusion (IR) injury is not precisely understood. Our study showed that in [...] Read more.

Trem2, a transmembrane protein that is simultaneously expressed in both bone marrow-derived and embryonic-derived liver-resident macrophages, plays a complex role in liver inflammation. The unique role of myeloid Trem2 in hepatic ischemia-reperfusion (IR) injury is not precisely understood. Our study showed that in the early stage of inflammation induction after IR, Deletion of myeloid Trem2 inhibited the induction of iNOS, MCP-1, and CXCL1/2, alleviated the accumulation of neutrophils and mitochondrial damage, and simultaneously decreased ROS formation. However, when inflammatory monocyte-macrophages gradually evolved into CD11b^hiLy6C_low pro-resolution macrophages through a phenotypic switch, the story of Trem2 took a turn. Myeloid Trem2 in pro-resolution macrophages promotes phagocytosis of IR-accumulated apoptotic cells by controlling Rac1-related actin polymerization, thereby actively promoting the resolution of inflammation. This effect may be exercised to regulate the Cox2/PGE2 axis by Trem2, alone or synergistically with MerTK/Arg1. Importantly, when myeloid Trem2 was over-expressed, the phenotypic transition of monocytes from a pro-inflammatory to a resolution type was accelerated, whereas knockdown of myeloid Trem2 resulted in delayed upregulation of CX3CR1. Collectively, our findings suggest that myeloid Trem2 is involved in the cascade of IR inflammation in a two-sided capacity, with complex and heterogeneous roles at different stages, not only contributing to our understanding of sterile inflammatory immunity but also to better explore the regulatory strategies and intrinsic requirements of targeting Trem2 in the event of sterile liver injury. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Liver Diseases)

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15 pages, 3485 KiB  

Open AccessArticle

FNDC5/Irisin Inhibits the Inflammatory Response and Mediates the Aerobic Exercise-Induced Improvement of Liver Injury after Myocardial Infarction

by Tao Wang, Mengyuan Yu, Hangzhuo Li, Shuguang Qin, Wujing Ren, Yixuan Ma, Wenyan Bo, Yue Xi, Mengxin Cai and Zhenjun Tian

Int. J. Mol. Sci. 2023, 24(4), 4159; https://doi.org/10.3390/ijms24044159 - 19 Feb 2023

Cited by 5 | Viewed by 1915

Abstract

Myocardial infarction (MI) causes peripheral organ injury, in addition to cardiac dysfunction, including in the liver, which is known as cardiac hepatopathy. Aerobic exercise (AE) can effectively improve liver injury, although the mechanism and targets are currently not well established. Irisin, mainly produced [...] Read more.

Myocardial infarction (MI) causes peripheral organ injury, in addition to cardiac dysfunction, including in the liver, which is known as cardiac hepatopathy. Aerobic exercise (AE) can effectively improve liver injury, although the mechanism and targets are currently not well established. Irisin, mainly produced by cleavage of the fibronectin type III domain-containing protein 5 (FNDC5), is a responsible for the beneficial effects of exercise training. In this study, we detected the effect of AE on MI-induced liver injury and explored the role of irisin alongside the benefits of AE. Wildtype and Fndc5 knockout mice were used to establish an MI model and subjected to AE intervention. Primary mouse hepatocytes were treated with lipopolysaccharide (LPS), rhirisin, and a phosphoinositide 3-kinase (PI3K) inhibitor. The results showed that AE significantly promoted M2 polarization of macrophages and improved MI-induced inflammation, upregulated endogenous irisin protein expression and activated the PI3K/ protein kinase B (Akt) signaling pathway in the liver of MI mice, while knockout of Fndc5 attenuated the beneficial effects of AE. Exogenous rhirisin significantly inhibited the LPS-induced inflammatory response, which was attenuated by the PI3K inhibitor. These results suggest that AE could effectively activate the FNDC5/irisin-PI3K/Akt signaling pathway, promote the polarization of M2 macrophages, and inhibit the inflammatory response of the liver after MI. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Liver Diseases)

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20 pages, 8537 KiB  

Open AccessArticle

HCC: RNA-Sequencing in Cirrhosis

by Haoyu Wang, Wenjie Shi, Jing Lu, Yuan Liu, Wei Zhou, Zekun Yu, Shengying Qin and Junwei Fan

Biomolecules 2023, 13(1), 141; https://doi.org/10.3390/biom13010141 - 10 Jan 2023

Cited by 1 | Viewed by 2015

Abstract

Hepatocellular carcinoma (HCC) ranks the most common types of cancer worldwide. As the fourth leading cause of cancer-related deaths, its prognosis remains poor. Most patients developed HCC on the basis of chronic liver disease. Cirrhosis is an important precancerous lesion for HCC. However, [...] Read more.

Hepatocellular carcinoma (HCC) ranks the most common types of cancer worldwide. As the fourth leading cause of cancer-related deaths, its prognosis remains poor. Most patients developed HCC on the basis of chronic liver disease. Cirrhosis is an important precancerous lesion for HCC. However, the molecular mechanisms in HCC development are still unclear. To explore the changes at the level of transcriptome in this process, we performed RNA-sequencing on cirrhosis, HCC and paracancerous tissues. Continuously changing mRNA was identified using Mfuzz cluster analysis, then their functions were explored by enrichment analyses. Data of cirrhotic HCC patients were obtained from TCGA, and a fatty acid metabolism (FAM)-related prognostic signature was then established. The performance and immunity relevance of the signature were verified in internal and external datasets. Finally, we validated the expression and function of ADH1C by experiments. As a result, 2012 differently expressed mRNA were identified by RNA-sequencing and bioinformatics analyses. Fatty acid metabolism was identified as a critical pathway by enrichment analyses of the DEGs. A FAM-related prognostic model and nomogram based on it were efficient in predicting the prognosis of cirrhotic HCC patients, as patients with higher risk scores had shorter survival time. Risk scores calculated by the signature were then proved to be associated with a tumor immune environment. ADH1C were downregulated in HCC, while silence of ADH1C could significantly promote proliferation and motility of the HCC cell line. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Liver Diseases)

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23 pages, 7726 KiB  

Open AccessArticle

Nucleophagic Degradation of Progerin Ameliorates Defenestration in Liver Sinusoidal Endothelium Due to SIRT1-Mediated Deacetylation of Nuclear LC3

by Yangqiu Bai, Jinying Liu, Xiaoke Jiang, Xiuling Li, Bingyong Zhang and Xiaoying Luo

Cells 2022, 11(23), 3918; https://doi.org/10.3390/cells11233918 - 03 Dec 2022

Cited by 2 | Viewed by 1571

Abstract

Progerin, a permanently farnesylated prelamin A protein in cell nuclei, is potentially implicated in the defenestration of liver sinusoidal endothelial cells (LSECs) and liver fibrogenesis. Autophagy regulates the degradation of nuclear components, called nucleophagy, in response to damage. However, little is known about [...] Read more.

Progerin, a permanently farnesylated prelamin A protein in cell nuclei, is potentially implicated in the defenestration of liver sinusoidal endothelial cells (LSECs) and liver fibrogenesis. Autophagy regulates the degradation of nuclear components, called nucleophagy, in response to damage. However, little is known about the role of nucleophagy in LSEC defenestration. Herein, we aim to dissect the underlying mechanism of progerin and nucleophagy in LSEC phenotype. We found an abnormal accumulation of progerin and a loss of SIRT1 in the nucleus of intrahepatic cells in human fibrotic liver tissue. In vivo, nuclear progerin abnormally accumulated in defenestrated LSECs, along with a depletion of SIRT1 and Cav-1 during liver fibrogenesis, whereas these effects were reversed by the overexpression of SIRT1 with the adenovirus vector. In vitro, H₂O₂ induced the excessive accumulation of progeirn, with the depletion of Lamin B1 and Cav-1 to aggravate LSEC defenestration. NAC and mito-TEMPO, classical antioxidants, inhibited NOX2- and NOX4-dependent oxidative stress to improve the depletion of Lamin B1 and Cav-1 and promoted progerin-related nucleophagy, leading to a reverse in H₂O₂-induced LSEC defenestration. However, rapamycin aggravated the H₂O₂-induced depletion of Lamin B1 and Cav-1 due to excessive autophagy, despite promoting progerin nucleophagic degradation. In addition, overexpressing SIRT1 with the adenovirus vector inhibited oxidative stress to rescue the production of Lamin B1 and Cav-1. Moreover, the SIRT1-mediated deacetylation of nuclear LC3 promoted progerin nucleophagic degradation and subsequently inhibited the degradation of Lamin B1 and Cav-1, as well as improved F-actin remodeling, contributing to maintaining LSEC fenestrae. Hence, our findings indicate a new strategy for reversing LSEC defenestration by promoting progerin clearance via the SIRT1-mediated deacetylation of nuclear LC3. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Liver Diseases)

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12 pages, 1554 KiB  

Open AccessArticle

Nonalcoholic Steatohepatitis: A 9-Year Follow Up Cohort Study

by Alessandra Mangia, Annarita Valeria Piazzolla, Maria Maddalena Squillante, Giovanna Cocomazzi, Vanna Maria Valori, Massimiliano Copetti, Paola Parente, Vito Attino and Maria Guido

J. Clin. Med. 2022, 11(19), 5969; https://doi.org/10.3390/jcm11195969 - 10 Oct 2022

Viewed by 1337

Abstract

Background and aim: Non-alcoholic fatty liver disease (NAFLD) may progress to severe liver fibrosis and cirrhosis. A limited number of studies with a long follow up assessed fibrosis progression and related predictors in untreated patients with a histological diagnosis of NAFLD. This study [...] Read more.

Background and aim: Non-alcoholic fatty liver disease (NAFLD) may progress to severe liver fibrosis and cirrhosis. A limited number of studies with a long follow up assessed fibrosis progression and related predictors in untreated patients with a histological diagnosis of NAFLD. This study aims to investigate rate and predictors of NAFLD progression. Methods: For 9 (2–16.7) years, we followed up a cohort of patients histologically diagnosed. Disease progression was defined by a composite endpoint as evidence of cirrhosis in patients without cirrhosis at baseline, evidence of de novo occurrence of cirrhosis complications, histologically established worsening of stage 1 of fibrosis or increase of 20% in liver stiffness by transient elastography in patients rejecting a second liver biopsy. Results: A total of 91 patients were enrolled. Of them, 31 had NAFL and 60 NASH. A second liver biopsy was performed in 22 NASH patients and in 4 NAFL. Disease progression was observed in 38.5% NASH and in 12.0% NAFL (p = 0.034). Patients with portal inflammation had a higher risk of progression (66.7% vs 26%, p = 0.021). High triglycerides levels, advanced fibrosis at baseline and the duration of follow-up predict disease progression (p = 0.021; OR = 6.93, 95% CI 1.33–36.08, p = 0.43; OR 8.37; 95% CI 1.07–65.58 and p = 0.034; OR = 0.88; 95% CI 0.78–0.99, respectively). Conclusions: Our results reinforce the evidence that, in the absence of pharmacologic treatment, NASH progresses in about 40% of patients. Liver biopsy is the only mean to discriminate NAFL from NASH. The prognostic role of portal inflammation needs to be explored in larger series. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Liver Diseases)

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