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Succinate‐GPR‐91 receptor signalling is responsible for nonalcoholic steatohepatitis‐associated fibrosis: Effects of DHA supplementation
Author(s) -
Liu XueJing,
Xie Li,
Du Kuo,
Liu Chang,
Zhang NingPing,
Gu ChenJian,
Wang Ying,
Abdelmalek Manal F.,
Dong WenYue,
Liu XiuPing,
Niu Chen,
Yang Chen,
Diehl Anna Mae,
Wu Jian
Publication year - 2020
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.14370
Subject(s) - lipotoxicity , fibrosis , hepatic stellate cell , steatohepatitis , medicine , endocrinology , receptor , docosahexaenoic acid , biology , chemistry , fatty liver , biochemistry , diabetes mellitus , fatty acid , polyunsaturated fatty acid , insulin resistance , disease
Background and aims Treatment of non‐alcoholic steatohepatitis (NASH) is challenging, because suppressing fibrotic progression has not been achieved consistently by drug candidates currently in clinical trials. The aim of this study was to investigate the molecular interplays underlying NASH‐associated fibrosis in a mouse NASH model and human specimens. Methods Mice were divided into 4 groups: Controls; NASH (high fat/Calorie diet plus high fructose and glucose in drinking water, HFCD‐HF/G) for 16 weeks; HFCD‐HF/G plus docosahexaenoic acid (DHA) for 16 or 8 weeks. Results Along with NASH progression, fibrotic deposition was documented in HFCD‐HF/G‐fed mice. Liver succinate content was significantly increased along with decreased expression of succinate dehydrogenase‐A (SDH‐A) in these mice; whereas, GPR‐91 receptor expression was much enhanced in histology compared to control mice, and co‐localized histologically with hepatic stellate cells (HSCs). Succinate content was increased in fatty acid‐overloaded primary hepatocytes with significant oxidant stress and lipotoxicity. Exposure to succinate led to up‐regulation of GPR‐91 receptor in primary and immortalized HSCs. In contrast, suppression of GPR‐91 receptor expression abolished succinate stimulatory role in GPR‐91 expression and extracellular matrix production in HSCs. All these changes were minimized or abrogated by DHA supplementation in vivo or in vitro. Moreover, GPR‐91 receptor expression correlates with severity of fibrosis in human NASH biopsy specimens. Conclusion Succinate accumulation in steatotoic hepatocytes may result in HSC activation through GPR‐91 receptor signalling in NASH progression, and the cross‐talk between hepatocytes and HSC through GPR‐91 signalling is most likely to be the molecular basis of fibrogenesis in NASH.