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 |
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Authors: | Xiaofei Zhu Xin Jia Fangyun Cheng Haimeng Tian Yajun Zhou |
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Affiliation: | 1. Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Nantong, PR China Equal-first authorship.;2. Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Nantong, PR China |
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Abstract: | 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. |
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Keywords: | hyperleptinemia obesity liver fibrosis AKT methionine adenosyltransferase |
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