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c‐Jun acts downstream of PI3K / AKT signaling to mediate the effect of leptin on methionine adenosyltransferase 2B in hepatic stellate cells in vitro and in vivo
Author(s) -
Zhu Xiaofei,
Jia Xin,
Cheng Fangyun,
Tian Haimeng,
Zhou Yajun
Publication year - 2020
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5536
Subject(s) - leptin , leptin receptor , chemistry , pi3k/akt/mtor pathway , hepatic stellate cell , endocrinology , medicine , socs3 , signal transduction , microbiology and biotechnology , cancer research , biology , stat3 , obesity
Obese patients, often accompanied by hyperleptinemia, are prone to develop liver fibrosis. A large body of data including the results from human studies suggested the promotion role of leptin, an adipocyte‐derived hormone, in liver fibrosis. Hepatic stellate cell (HSC) activation, a crucial step in liver fibrogenesis, requires global reprogramming of gene expression which is regulated by multiple mechanisms including epigenetic regulation such as methylation of DNA. S ‐Adenosylmethionine is a principal biological methyl donor and its biosynthesis is catalyzed by a methionine adenosyltransferase (MAT) such as MATII. MATII consists of the catalytic subunit MAT2A and regulatory subunit MAT2B which are essential for HSC activation. The present research investigated the effect of leptin on the expression of Mat2b in HSCs in vitro and in a leptin‐deficient mouse model. Results demonstrated that leptin significantly increased Mat2b expression. Leptin‐induced Mat2b expression required the PI3K/AKT signaling pathway. c‐Jun, a component of activator protein (AP1), was phosphorylated by leptin‐induced PI3K/AKT signaling and thus potentiated its binding to the element around −964 bp in the Mat2b promoter. MAT2B was involved in leptin‐induced HSC activation and liver fibrosis in a leptin‐deficient mouse model. These results might broaden understanding of the mechanisms underlying the liver fibrogenesis in obese patients with hyperleptinemia. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.