Cholesterol Induces Oxidative Stress, Mitochondrial Damage and Death in Hepatic Stellate Cells to Mitigate Liver Fibrosis in Mice Model of NASH

Einat Rauchbach, Haim Zeigerman, Diana Abu-Halaka, Oren Tirosh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Liver fibrosis and its end-stage disease cirrhosis are major world health problems arising from chronic injury of the liver. In recent years, the hypothesis that hepatic stellate cells’ (HSCs’) activation and fibrosis can be mitigated by HSC apoptosis and cell death has become of interest. In the current study, we evaluated the effect of cholesterol and bile acids on HSC apoptosis and liver fibrosis. Male C57BL/6J mice (wild type), aged four to five weeks, were fed an AIN-93G based diet (normal diet, ND), ND diet + 1% (w/w) cholesterol (CHOL group), ND diet + 0.5% (w/w) cholic acid (CA group) or ND diet + 1% (w/w) cholesterol + 0.5% (w/w) cholic acid (CHOL + CA group). Female Mdr2(-/-) mice were also treated with ND with and without 1% cholesterol. The effect of cholesterol on liver fibrosis and als treated with cholic acids, increased lipid peroxidation and fibrosis were observed after six weeks of treatment. However, addition of cholesterol to the diet of C57BL/6J mice led to HSC-specific apoptosis and resolution of liver fibrosis, verified by double-staining with active caspase and α smooth muscle actin antibodies. In Mdr2 (-/-) mice, a diet supplemented with cholesterol corrected fibrosis and induced active hepatic stellate cells’ clearance. HSC-T6 were found to be much more sensitive to cholesterol-induced oxidative stress, mitochondrial damage and apoptosis compared to hepatocytes. These results indicate that cholesterol may be a trigger of HSC lipid peroxidation and death in the liver in a model of non-alcoholic steatohepatitis. A high cholesterol-to-bile acid ratio may determine the trajectory of the liver disease toward mitigation of fibrosis.

Original languageAmerican English
Article number536
JournalAntioxidants
Volume11
Issue number3
DOIs
StatePublished - Mar 2022

Bibliographical note

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Fibrosis
  • Lipid peroxidation
  • Liver disease
  • apoptosis

Fingerprint

Dive into the research topics of 'Cholesterol Induces Oxidative Stress, Mitochondrial Damage and Death in Hepatic Stellate Cells to Mitigate Liver Fibrosis in Mice Model of NASH'. Together they form a unique fingerprint.

Cite this