Microbiota-induced lipid peroxidation impairs obeticholic acid-mediated antifibrotic effect towards nonalcoholic steatohepatitis in mice
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 induce...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-02-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231722003548 |
| _version_ | 1797954075223916544 |
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| author | Aoxiang Zhuge Shengjie Li Yin Yuan Shengyi Han Jiafeng Xia Qiangqiang Wang Shuting Wang Pengcheng Lou Bo Li Lanjuan Li |
| author_facet | Aoxiang Zhuge Shengjie Li Yin Yuan Shengyi Han Jiafeng Xia Qiangqiang Wang Shuting Wang Pengcheng Lou Bo Li Lanjuan Li |
| author_sort | Aoxiang Zhuge |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T23:12:57Z |
| format | Article |
| id | doaj.art-08ec162d082443878686b3914be767c0 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-10T23:12:57Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-08ec162d082443878686b3914be767c02023-01-13T04:16:19ZengElsevierRedox Biology2213-23172023-02-0159102582Microbiota-induced lipid peroxidation impairs obeticholic acid-mediated antifibrotic effect towards nonalcoholic steatohepatitis in miceAoxiang Zhuge0Shengjie Li1Yin Yuan2Shengyi Han3Jiafeng Xia4Qiangqiang Wang5Shuting Wang6Pengcheng Lou7Bo Li8Lanjuan Li9State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, ChinaState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China; Corresponding author. Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China.State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China; Jinan Microecological Biomedicine Shandong Laboratory, Jinan, 250000, China; Corresponding author. Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Beijing, 100730, China.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.http://www.sciencedirect.com/science/article/pii/S2213231722003548 |
| spellingShingle | Aoxiang Zhuge Shengjie Li Yin Yuan Shengyi Han Jiafeng Xia Qiangqiang Wang Shuting Wang Pengcheng Lou Bo Li Lanjuan Li Microbiota-induced lipid peroxidation impairs obeticholic acid-mediated antifibrotic effect towards nonalcoholic steatohepatitis in mice Redox Biology |
| title | Microbiota-induced lipid peroxidation impairs obeticholic acid-mediated antifibrotic effect towards nonalcoholic steatohepatitis in mice |
| title_full | Microbiota-induced lipid peroxidation impairs obeticholic acid-mediated antifibrotic effect towards nonalcoholic steatohepatitis in mice |
| title_fullStr | Microbiota-induced lipid peroxidation impairs obeticholic acid-mediated antifibrotic effect towards nonalcoholic steatohepatitis in mice |
| title_full_unstemmed | Microbiota-induced lipid peroxidation impairs obeticholic acid-mediated antifibrotic effect towards nonalcoholic steatohepatitis in mice |
| title_short | Microbiota-induced lipid peroxidation impairs obeticholic acid-mediated antifibrotic effect towards nonalcoholic steatohepatitis in mice |
| title_sort | microbiota induced lipid peroxidation impairs obeticholic acid mediated antifibrotic effect towards nonalcoholic steatohepatitis in mice |
| url | http://www.sciencedirect.com/science/article/pii/S2213231722003548 |
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