Involvement of Rho/Rho kinase pathway in regulation of apoptosis in rat hepatic stellate cells

Hepatic stellate cells (HSCs) play a central role in the development of hepatic fibrosis. Recent evidence has revealed that HSCs also play a role in its resolution, where HSC apoptosis was determined. Moreover, induction of HSC apoptosis caused a reduction of experimental hepatic fibrosis in rats. Thus knowing the mechanism of HSC apoptosis might be important to clarify the pathophysiology and establish the therapeutic strategy for hepatic fibrosis. In HSCs, Rho and Rho kinase are known to regulate contraction, migration, and proliferation with modulation of cell morphology. Controversy exists as to the participation of Rho and Rho kinase on cell survival, and little is known regarding this matter in HSCs. In this study, we directed our focus on the role of the Rho pathway in the regulation of HSC survival. C3, an inhibitor of Rho, increased histone-associated DNA fragmentation and caspase 3 activity with enhanced condensation of nuclear chromatin in rat cultured HSCs. Moreover, Y-27632, an inhibitor of Rho kinase, had the same effects, suggesting that inhibition of the Rho/Rho kinase pathway causes HSC apoptosis. On the other hand, lysophosphatidic acid, which stimulates the Rho/Rho kinase pathway, decreased histone-associated DNA fragmentation in HSCs. Inhibition of the Rho/Rho kinase pathway did not affect p53, Bcl-2, or Bax levels in HSCs. Thus we concluded that the Rho/Rho kinase pathway may play a role in the regulation of HSC survival.

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Inhibition of SIRT2 suppresses hepatic fibrosis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00271.2015 ◽

2016 ◽

Vol 310 (11) ◽

pp. G1155-G1168 ◽

Cited By ~ 17

Author(s):

Maribel Arteaga ◽

Na Shang ◽

Xianzhong Ding ◽

Sherri Yong ◽

Scott J. Cotler ◽

...

Keyword(s):

Gene Expression ◽

Liver Fibrosis ◽

Hepatic Fibrosis ◽

Hepatic Stellate Cells ◽

Histone Deacetylases ◽

Critical Role ◽

Stellate Cells ◽

Novel Strategy ◽

Underlying Mechanisms

Liver fibrosis can progress to cirrhosis and result in serious complications of liver disease. The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs), the underlying mechanisms of which are not fully known. Emerging evidence suggests that the classic histone deacetylases play a role in liver fibrosis, but the role of another subfamily of histone deacetylases, the sirtuins, in the development of hepatic fibrosis remains unknown. In this study, we found that blocking the activity of sirtuin 2 (SIRT2) by using inhibitors or shRNAs significantly suppressed fibrogenic gene expression in HSCs. We further demonstrated that inhibition of SIRT2 results in the degradation of c-MYC, which is important for HSC activation. In addition, we discovered that inhibition of SIRT2 suppresses the phosphorylation of ERK, which is critical for the stabilization of c-MYC. Moreover, we found that Sirt2 deficiency attenuates the hepatic fibrosis induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). Furthermore, we showed that SIRT2, p-ERK, and c-MYC proteins are all overexpressed in human hepatic fibrotic tissues. These data suggest a critical role for the SIRT2/ERK/c-MYC axis in promoting hepatic fibrogenesis. Inhibition of the SIRT2/ERK/c-MYC axis represents a novel strategy to prevent and to potentially treat liver fibrosis and cirrhosis.

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Hepatic stellate cells-specific Loxl1 deficiency abrogates hepatic inflammation, fibrosis, and corrects lipid metabolic abnormalities in non-obese NASH mice

10.21203/rs.3.rs-260786/v1 ◽

2021 ◽

Author(s):

Aiting Yang ◽

Xuzhen Yan ◽

Xu Fan ◽

Yiwen Shi ◽

Tao Huang ◽

...

Keyword(s):

Hepatic Stellate Cells ◽

Therapeutic Strategy ◽

Potential Role ◽

Lysyl Oxidase ◽

Control Diet ◽

Stellate Cells ◽

Metabolic Abnormalities ◽

Deficient Mice ◽

Specific Deletion

Abstract Background & Aims: Lysyl oxidase-like-1 (LOXL1), a vital crosslinking enzyme in extracellular matrix (ECM) protein maintenance, is well established in fibrosis via mediating ECM stabilization. However, the potential role of LOXL1 in the pathogenesis of nonalcoholic steatohepatitis (NASH) has not been previously studied.Methods: We generated Loxl1fl/fl mice to selectively delete Loxl1 in hepatic stellate cells (HSCs) (Loxl1fl/flGfapcre; Loxl1fl/fl as littermate controls) and then examined liver pathology and metabolic context in Loxl1fl/flGfapcre fed a choline-deficient L-amino acid-defined (CDAA) diet or an isocaloric control diet for 16 weeks. We confirmed study findings in 23 patients with biopsy-proven NAFLD.Results: LOXL1 was significantly increased in CDAA induced non-obese NASH compared with control diet. Here, utilizing a HSCs-specific deletion of Loxl1 model, we found that Loxl1 deficient in HSCs ameliorated CDAA-induced inflammation and fibrosis, with reduced expression of pro-inflammation and pro-fibrogenic genes. Interestingly, CDAA-fed Loxl1 deficient mice was associated with improved body weight and attenuated hepatic steatosis and to an up-regulation of leptin in adipose tissue and in serum, without changes in hepatic lipogenesis gene expression, compared with CDAA-fed control mice. Most importantly, analyses of serum LOXL1 and leptin levels from NAFLD patients revealed that LOXL1 was positively correlated with histological fibrosis progression, whereas was inversely correlated with leptin levels, especially in non-obese NAFLD patients.Conclusion: In a mouse model of CDAA-induced non-obese NASH, selective deletion of Loxl1 from HSCs attenuated steatohepatitis, hepatic fibrosis and improved lipid metabolic abnormalities. Hence, LOXL1 inhibition may serve as a new therapeutic strategy for NASH.

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Role of G Protein-Coupled Receptors in Hepatic Stellate Cells and Approaches to Anti-Fibrotic Treatment of Non-Alcoholic Fatty Liver Disease

Frontiers in Endocrinology ◽

10.3389/fendo.2021.773432 ◽

2021 ◽

Vol 12 ◽

Author(s):

Takefumi Kimura ◽

Simran Singh ◽

Naoki Tanaka ◽

Takeji Umemura

Keyword(s):

Liver Disease ◽

Hepatic Fibrosis ◽

Hepatic Stellate Cells ◽

Fatty Liver Disease ◽

Stellate Cells ◽

G Protein Coupled Receptors ◽

Alcoholic Fatty Liver ◽

G Protein Coupled ◽

Alcoholic Fatty Liver Disease

The prevalence of non-alcoholic fatty liver disease (NAFLD) is globally increasing. Gaining control over disease-related events in non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD, is currently an unmet medical need. Hepatic fibrosis is a critical prognostic factor in NAFLD/NASH. Therefore, a better understanding of the pathophysiology of hepatic fibrosis and the development of related therapies are of great importance. G protein-coupled receptors (GPCRs) are cell surface receptors that mediate the function of a great variety of extracellular ligands. GPCRs represent major drug targets, as indicated by the fact that about 40% of all drugs currently used in clinical practice mediate their therapeutic effects by acting on GPCRs. Like many other organs, various GPCRs play a role in regulating liver function. It is predicted that more than 50 GPCRs are expressed in the liver. However, our knowledge of how GPCRs regulate liver metabolism and fibrosis in the different cell types of the liver is very limited. In particular, a better understanding of the role of GPCRs in hepatic stellate cells (HSCs), the primary cells that regulate liver fibrosis, may lead to the development of drugs that can improve hepatic fibrosis in NAFLD/NASH. In this review, we describe the functions of multiple GPCRs expressed in HSCs, their roles in liver fibrogenesis, and finally speculate on the development of novel treatments for NAFLD/NASH.

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Autophagy in Hepatic Fibrosis

BioMed Research International ◽

10.1155/2014/436242 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 19

Author(s):

Yang Song ◽

Yingying Zhao ◽

Fei Wang ◽

Lichan Tao ◽

Junjie Xiao ◽

...

Keyword(s):

Hepatic Fibrosis ◽

Hepatic Stellate Cells ◽

Liver Diseases ◽

Metabolic Disorders ◽

Therapeutic Strategy ◽

Stellate Cells ◽

Protective Role ◽

Chronic Liver Diseases ◽

Near Future ◽

Novel Therapeutic

Hepatic fibrosis is a leading cause of morbidity and mortality worldwide. Hepatic fibrosis is usually associated with chronic liver diseases caused by infection, drugs, metabolic disorders, or autoimmune imbalances. Effective clinical therapies are still lacking. Autophagy is a cellular process that degrades damaged organelles or protein aggregation, which participates in many pathological processes including liver diseases. Autophagy participates in hepatic fibrosis by activating hepatic stellate cells and may participate as well through influencing other fibrogenic cells. Besides that, autophagy can induce some liver diseases to develop while it may play a protective role in hepatocellular abnormal aggregates related liver diseases and reduces fibrosis. With a better understanding of the potential effects of autophagy on hepatic fibrosis, targeting autophagy might be a novel therapeutic strategy for hepatic fibrosis in the near future.

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Lysophosphatidic Acid Enhances Collagen Gel Contraction by Hepatic Stellate Cells: Association with Rho-Kinase

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.2000.3634 ◽

2000 ◽

Vol 277 (1) ◽

pp. 72-78 ◽

Cited By ~ 59

Author(s):

Mikio Yanase ◽

Hitoshi Ikeda ◽

Atsushi Matsui ◽

Hisato Maekawa ◽

Eisei Noiri ◽

...

Keyword(s):

Lysophosphatidic Acid ◽

Hepatic Stellate Cells ◽

Rho Kinase ◽

Collagen Gel ◽

Stellate Cells ◽

Collagen Gel Contraction

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Role of microRNAs in Hepatic Stellate Cells and Hepatic Fibrosis: an Update

Current Pharmaceutical Design ◽

10.2174/1381612826666201023143542 ◽

2020 ◽

Vol 26 ◽

Author(s):

Sai Zhu ◽

Xin Chen ◽

Yu Chen ◽

Xiao-Feng Li ◽

Si-Yu Chen ◽

...

Keyword(s):

Hepatic Fibrosis ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Pathological Process ◽

Untranslated Regions ◽

Rna Molecules ◽

Non Coding Rna ◽

Major Cell Type ◽

Novel Biomarkers

: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of targets genes by binding to the 3′-untranslated regions. They play vital roles in diverse biological processes, including the development of hepatic fibrosis (HF). HF is characterized by the accumulation of extracellular matrix (ECM) and hepatic stellate cells (HSCs) are considered a major cell type for producing ECM. Alteration of the HSC phenotype plays a crucial role in the HF pathological process. miRNAs involved in various biological process, such as differentiation, apoptosis, migration, and their relevant signaling pathways, are expressed in HSCs; however, emerging evidence indicates that numerous miRNAs are abnormally expressed in activated HSCs. In this review, we summarize the categorization of miRNAs in HF and describe the relationships among them. We also discuss miRNAs recently discovered to be related to HF, and attempt to find potential miRNAs that may serve as novel biomarkers for use in HF treatment.

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PPARγ Antagonizes Hypoxia-Induced Activation of Hepatic Stellate Cell through Cross Mediating PI3K/AKT and cGMP/PKG Signaling

PPAR Research ◽

10.1155/2018/6970407 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Qinghui Zhang ◽

Shihao Xiang ◽

Qingqian Liu ◽

Tao Gu ◽

Yongliang Yao ◽

...

Keyword(s):

Hepatic Fibrosis ◽

Hepatic Stellate Cells ◽

Stellate Cell ◽

Stellate Cells ◽

Inhibitory Effect ◽

Akt Signaling ◽

Unique Role ◽

Hypoxic Environment ◽

Sirius Red

Background and Aims. Accumulating evidence reveals that PPARγ plays a unique role in the regulation of hepatic fibrosis and hepatic stellate cells (HSCs) activation. This study was aimed at investigating the role of PPARγ in hypoxia-induced hepatic fibrogenesis and its possible mechanism. Methods. Rats used for CCl4-induced hepatic fibrosis model were exposed to hypoxia for 8 hours each day. Rats exposed to hypoxia were treated with or without the PPARγ agonist rosiglitazone. Liver sections were stained with HE and Sirius red staining 8 weeks later. HSCs were exposed to hypoxic environment in the presence or absence of rosiglitazone, and expression of PPARγ and two fibrosis markers, α-SMA and desmin, were measured using western blot and immunofluorescence staining. Next, levels of PPARγ, α-SMA, and desmin as well as PKG and cGMP activity were detected using PI3K/AKT and a cGMP activator or inhibitor. Results. Hypoxia promoted the induction and progress of hepatic fibrosis and HSCs activation. Meanwhile, rosiglitazone significantly antagonized the effects induced by hypoxia. Signaling by sGC/cGMP/PKG promoted the inhibitory effect of PPARγ on hypoxia-induced activation of HSCs. Moreover, PI3K/AKT signaling or PDE5 blocked the above response of PPARγ. Conclusion. sGC/cGMP/PKG and PI3K/AKT signals act on PPARγ synergistically to attenuate hypoxia-induced HSC activation.

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