Resveratrol inhibited hepatocyte apoptosis and alleviated liver fibrosis through miR-190a-5p /HGF axis

Sphingosine kinase 1 (SphK1)/Sphingosine-1-phosphate (S1P)/S1PRs signaling pathway is known to involve the advancement of liver fibrosis. Exosomal SphK1 promotes hepatic stellate cells (HSC) migration. Salidroside (Sal) inhibits liver fibrosis, but its mechanism is yet to be elucidated. This study was to explore the influences of Sal on the SphK/S1P/S1PRs signaling pathway in liver fibrosis induced by carbon tetrachloride (CCl4) in vivo, and investigated the mechanism of Sal affecting the migration and activation of HSC triggered by exosomal SphK1 in vitro. Our data showed that Sal reduced the activities of alanine transaminase (ALT), aspartate aminotransferase (AST) in serum, and hydroxyproline (Hyp) content in the liver tissue. Sal subdued the expression of α-smooth muscle actin (α-SMA), fibronectin (FN) and type I collagen (Col I) of the liver. Sal also reduced mitochondria-induced hepatocyte apoptosis and to inhibit JNK activation. Furthermore, Sal remarkably eradicated the influence of SphK1, SphK2, S1P, and S1PRs triggered by CCl4, whether stimulating or hindering. Compared with serum-derived exosomes from model group mice, serum-derived exosomes from Sal group mice expressed lower SphK1 and reduced JS 1 (mouse HSC cell line) migration. In addition, Sal was also observed to subdue Col I expression, AKT activation, and LX-2 migration induced by exosomal SphK1 from SK-HEP-1 (a kind of liver sinusoidal endothelial cells (LSEC) cell line). In conclusion, Sal could effectively alleviate liver injury, hepatocyte apoptosis, and liver fibrosis in vivo, providing supports that the protective effects of Sal might be realized by suppressing JNK activation and modulating the SphK/S1P/S1PRs axis. In vitro, it was observed that Sal might alleviate LX-2 migration and activation induced by exosomal SphK1 by inhibiting the AKT activation.

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Downregulated long non-coding RNA LINC01093 in liver fibrosis promotes hepatocyte apoptosis via increasing ubiquitination of SIRT1

The Journal of Biochemistry ◽

10.1093/jb/mvaa013 ◽

2020 ◽

Vol 167 (5) ◽

pp. 525-534

Author(s):

Yinhe Tang ◽

Naijing Ma ◽

Hao Luo ◽

Shizuan Chen ◽

Fuxiang Yu

Keyword(s):

Liver Fibrosis ◽

Cell Apoptosis ◽

Hepatocyte Apoptosis ◽

Non Coding Rna ◽

Silent Information Regulator 1 ◽

Underlying Mechanisms ◽

Long Non Coding Rna ◽

Tgf Β1 ◽

Liver Tissues

Abstract The apoptosis of hepatocytes contributes to the activation of hepatic stellate cells (HSCs), thus promoting the accumulation of extracellular matrix proteins and aggravating liver fibrosis. Silent information regulator 1 (SIRT1) is an anti-fibrotic protein whose downregulation induces hepatocyte apoptosis. This study aims to identify whether SIRT1 is regulated by long non-coding RNA LINC01093 and explore its underlying mechanisms. Liver fibrosis was induced in mice using CCl4, and the differential expressions of several fibrosis-related long noncoding RNAs were detected in liver tissues. The effect of LINC01093 on cell apoptosis and viability of hepatocytes were investigated after LINC01093 overexpression or knockdown using flow cytometry and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The anti-fibrotic effect of LINC01093 overexpression was observed in vivo. LncRNA LINC01093 is downregulated in CCl4-induced liver tissues and TGF-β1-stimulated hepatocytes. Downregulated LINC01093 promoted cell apoptosis and inhibited cell viability of hepatocytes. The co-culture between LINC01093-knockdown hepatocytes and HSCs increased the expressions of pro-fibrotic proteins. Downregulated LINC01093 promoted hepatocyte apoptosis via promoting degradation and ubiquitination of SIRT1 under TGF-β1 stimulation. The injection of LINC01093-overexpressing vectors alleviated liver fibrosis in vivo. In liver fibrosis, the downregulated LINC01093 promoted hepatocyte apoptosis, which is mediated by increasing the degradation and ubiquitination of SIRT1.

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Camellia oil (Camellia oleifera Abel.) attenuates CCl4-induced liver fibrosis via suppressing hepatocyte apoptosis in mice

Food & Function ◽

10.1039/c9fo02258a ◽

2020 ◽

Vol 11 (5) ◽

pp. 4582-4590 ◽

Cited By ~ 2

Author(s):

Xiaohua Lei ◽

Qiang Liu ◽

Zhenyu Cao ◽

Ju Zhang ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Diseases ◽

Chronic Liver ◽

Camellia Oleifera ◽

Chronic Liver Diseases ◽

Hepatocyte Apoptosis ◽

Camellia Oil ◽

Common Part ◽

Pathological Development

Liver fibrosis is a common part of the pathological development of many chronic liver diseases.

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Sortilin Deficiency Reduces Ductular Reaction, Hepatocyte Apoptosis, and Liver Fibrosis in Cholestatic-Induced Liver Injury

American Journal Of Pathology ◽

10.1016/j.ajpath.2016.09.005 ◽

2017 ◽

Vol 187 (1) ◽

pp. 122-133 ◽

Cited By ~ 5

Author(s):

Einav Hubel ◽

Ashish Saroha ◽

Woo-Jae Park ◽

Yael Pewzner-Jung ◽

Elise G. Lavoie ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Hepatocyte Apoptosis ◽

Ductular Reaction

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Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2012.05.007 ◽

2012 ◽

Vol 53 (2) ◽

pp. 289-296 ◽

Cited By ~ 147

Author(s):

Joy X. Jiang ◽

Xiangling Chen ◽

Nobuko Serizawa ◽

Cédric Szyndralewiez ◽

Patrick Page ◽

...

Keyword(s):

Liver Fibrosis ◽

Hepatocyte Apoptosis

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P375 SORTILIN DEFICIENCY ABOLISHES DUCTULAR REACTION AND REDUCES HEPATOCYTE APOPTOSIS AND LIVER FIBROSIS IN BILE DUCT LIGATION-INDUCED CHOLESTASIS

Journal of Hepatology ◽

10.1016/s0168-8278(14)60537-7 ◽

2014 ◽

Vol 60 (1) ◽

pp. S193

Author(s):

I. Zvibel ◽

E. Hubel ◽

J. Dranoff ◽

W.J. Park ◽

E. Lavoie ◽

...

Keyword(s):

Bile Duct ◽

Liver Fibrosis ◽

Bile Duct Ligation ◽

Hepatocyte Apoptosis ◽

Ductular Reaction ◽

Duct Ligation

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A Novel Sox9/lncRNA H19 Axis Contributes to Hepatocyte Death and Liver Fibrosis

Toxicological Sciences ◽

10.1093/toxsci/kfaa097 ◽

2020 ◽

Vol 177 (1) ◽

pp. 214-225

Author(s):

Chenqi Wang ◽

Jia Deng ◽

Hao Deng ◽

Zhiqian Kang ◽

Zhen Huang ◽

...

Keyword(s):

Liver Fibrosis ◽

Noncoding Rna ◽

Animal Experiments ◽

Ectopic Expression ◽

Hepatocyte Apoptosis ◽

Fibrotic Liver ◽

Downstream Effector ◽

Hepatocyte Injury

Abstract Sox9 has been previously characterized as a transcription factor responsible for the extracellular matrix production during liver fibrosis. However, the deregulation and functional role of hepatocyte Sox9 in the progression of liver fibrosis remains elusive. Here, we found a significant increase of Sox9 in the hepatocytes isolated from CCl4-induced fibrotic liver and showed that antisense oligoribonucleotides depletion of Sox9 was sufficient to attenuate CCl4-induced liver fibrosis. Notably, the increase of Sox9 in hepatocyte was associated with the upregulation of long noncoding RNA H19 in both in vitro and in vivo systems. Mechanistic studies revealed that Sox9 induced H19 by binding to a conserved promoter region of H19. In vitro, hepatocyte injury triggered the increase of Sox9/H19 axis, whereas silence of H19 greatly alleviated the H2O2-induced hepatocyte apoptosis, suggesting that H19 functions as a downstream effector of Sox9 signaling and is involved in hepatocyte apoptosis. In animal experiments, inhibition of H19 alleviated the activation of hepatic stellate cells and reduced the extent of liver fibrosis, whereas ectopic expression of H19 abolished the inhibitory effects of Sox9 depletion on liver fibrosis, suggesting that the profibrotic effect of hepatocyte Sox9 depends on H19. Finally, we investigated the clinical relevance of Sox9/H19 axis to liver fibrosis and identified the increase of Sox9/H19 axis in liver cirrhosis patients. In conclusion, our findings link Sox9/H19 axis to the intrinsic mechanisms of hepatocyte apoptosis and may represent a hitherto unknown paradigm in hepatocyte injury associated with the progression of liver fibrosis.

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