Microbiota-induced lipid peroxidation impairs obeticholic acid-mediated antifibrotic effect towards nonalcoholic steatohepatitis in mice.

Abstract

Obeticholic acid (OCA) has been examined to treat non-alcoholic steatohepatitis (NASH), but has unsatisfactory antifibrotic effect and deficient responsive rate in recent phase III clinical trial. Using a prolonged western diet-feeding murine NASH model, we show that OCA-shaped gut microbiota induces lipid peroxidation and impairs its anti-fibrotic effect. Mechanically, Bacteroides enriched by OCA deconjugates tauro-conjugated bile acids to generate excessive chenodeoxycholic acid (CDCA), resulting in liver ROS accumulation. We further elucidate that OCA reduces triglycerides containing polyunsaturated fatty acid (PUFA-TGs) levels, whereas elevates free PUFAs and phosphatidylethanolamines containing PUFA (PUFA-PEs), which are susceptible to be oxidized to lipid peroxides (notably arachidonic acid (ARA)-derived 12-HHTrE), inducing hepatocyte ferroptosis and activating hepatic stellate cells (HSCs). Inhibiting lipid peroxidation with pentoxifylline (PTX) rescues anti-fibrotic effect of OCA, suggesting combination of OCA and lipid peroxidation inhibitor could be a potential antifibrotic pharmacological approach in clinical NASH-fibrosis.

• Authors: Aoxiang Zhuge, Shengjie Li, Yin Yuan, Shengyi Han, Jiafeng Xia, Qiangqiang Wang, Shuting Wang, Pengcheng Lou, Bo Li, Lanjuan Li
• Journal: Redox biology (Redox Biol) Vol. 59 Pg. 102582 (02 2023) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 36584600 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• obeticholic acid
• Chenodeoxycholic Acid

Topics

• Mice
• Animals
• Non-alcoholic Fatty Liver Disease (drug therapy, metabolism)
• Lipid Peroxidation
• Liver (metabolism)
• Chenodeoxycholic Acid (pharmacology, metabolism, therapeutic use)
• Microbiota