Aging enhances liver fibrotic response in mice through hampering extracellular matrix remodeling

Delire, Bénédicte; Lebrun, Valérie; Selvais, Charlotte; Henriet, Patrick; Bertrand, Anthony A.; Horsmans, Yves; Leclecrq, I.

doi:10.1016/s0168-8278(17)31756-7

Cited by 2 publications

(1 citation statement)

References 47 publications

(68 reference statements)

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“…A limitation of the present study is that it was conducted on young animals (3 and 4 months old at the time of sacrifice). Young animals have a different ECM composition, higher regenerative capacity, and higher collagen turnover rate compared to old animals . To address this issue, future studies using aged mice for evaluation of the RGD inhibitors are warranted.…”

Section: Discussionmentioning

confidence: 99%

An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis

et al. 2018

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The presence and stage of liver fibrosis in patients with nonalcoholic steatohepatitis (NASH) is strongly associated with mortality. Thus, both preventing and reversing fibrosis are critically important approaches to prevent death or the need for liver transplantation from NASH. Recently, fibrosis in several mouse models of organ injury was shown to be prevented and reversed with the potent small molecule, arginine‐glycine‐aspartic acid tripeptide (RGD)‐binding, integrin antagonist (3S)‐3‐(3‐bromo‐5‐(tert‐butyl)phenyl)‐3‐(2‐(3‐hydroxy‐5‐((5‐hydroxy‐1,4,5,6‐tetrahydropyrimidin‐2‐yl)amino)benzamido)acetamido)propanoic acid (Center for World Health and Medicine [CWHM]‐12). We hypothesized that RGD‐binding integrins may play an important role in fibrosis progression in NASH. We assessed the efficacy of CWHM‐12 in a choline deficient, amino‐acid defined, high‐fat diet (CDAHFD) mouse model of NASH. Mice were kept on the CDAHFD or a control diet for 10 weeks, and CWHM‐12 was delivered by continuous infusion for the final 4 weeks. The parameters of NASH and liver fibrosis were evaluated before and after drug treatment. Hepatic steatosis, liver injury, and inflammation were significantly induced by the CDAHFD at week 6 and did not change by week 10. Hepatic profibrogenic gene expression was induced by the CDAHFD at week 6, further increased at week 10, and decreased by CWHM‐12. Fibrosis measured by analysis of liver collagen was reduced by CWHM‐12 to levels significantly less than found at 6 weeks, demonstrating the possibility of reversing already established fibrosis despite ongoing injury. Demonstrated mechanisms of the antifibrotic effect of CWHM‐12 included loss of activated hepatic stellate cells through apoptosis and suppression of hepatic profibrotic signal transduction by transforming growth factor β. Conclusion: RGD‐binding integrins may be critical in the development of fibrosis in NASH and may represent potential targets for treating patients with NASH to reverse advanced liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis

et al. 2018

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Administration of Glutaredoxin-1 Attenuates Liver Fibrosis Caused by Aging and Non-Alcoholic Steatohepatitis

et al. 2022

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Liver fibrosis is a sign of non-alcoholic fatty liver disease progression towards steatohepatitis (NASH) and cirrhosis and is accelerated by aging. Glutaredoxin-1 (Glrx) controls redox signaling by reversing protein S-glutathionylation, induced by oxidative stress, and its deletion causes fatty liver in mice. Although Glrx regulates various pathways, including metabolism and apoptosis, the impact of Glrx on liver fibrosis has not been studied. Therefore, we evaluated the role of Glrx in liver fibrosis induced by aging or by a high-fat, high-fructose diet. We found that: (1) upregulation of Glrx expression level inhibits age-induced hepatic apoptosis and liver fibrosis. In vitro studies indicate that Glrx regulates Fas-induced apoptosis in hepatocytes; (2) diet-induced NASH leads to reduced expression of Glrx and higher levels of S-glutathionylated proteins in the liver. In the NASH model, hepatocyte-specific adeno-associated virus-mediated Glrx overexpression (AAV-Hep-Glrx) suppresses fibrosis and apoptosis and improves liver function; (3) AAV-Hep-Glrx significantly inhibits transcription of Zbtb16 and negatively regulates immune pathways in the NASH liver. In conclusion, the upregulation of Glrx is a potential therapeutic for the reversal of NASH progression by attenuating inflammatory and fibrotic processes.

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Aging enhances liver fibrotic response in mice through hampering extracellular matrix remodeling

Cited by 2 publications

References 47 publications

An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis

An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis

Administration of Glutaredoxin-1 Attenuates Liver Fibrosis Caused by Aging and Non-Alcoholic Steatohepatitis

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