Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Nantong, China.
Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China.
FASEB J. 2020 Apr;34(4):5578-5589. doi: 10.1096/fj.201903021RR. Epub 2020 Feb 28.
Most obese patients develop hyperleptinaemia. Leptin, mainly produced by adipocytes, demonstrates a promotional role in liver fibrosis. Hepatic stellate cell (HSC) activation, a key step in liver fibrogenesis, requires global reprogramming of gene expression. The remodeling of DNA methylation is a mechanism of the epigenetic regulation of gene expression. The biosynthesis of S-adenosylmethionine, a principle biological methyl donor, is catalyzed by methionine adenosyltransferase (MAT) such as MATⅡ which has been shown to promote HSC activation in vitro. This study was mainly aimed to determine the effect of leptin on MAT2A expression (the catalytic subunit of MATⅡ) in HSCs. Results showed that MAT2A knockdown reduced leptin-induced HSC activation and liver fibrosis in the leptin-deficient mouse model. Leptin promoted MAT2A expression in HSCs and increased MAT2A promoter activity. The axis of the β-catenin pathway/E2F-4 mediated the effect of leptin on MAT2A expression. Leptin-induced β-catenin signaling reduced E2F-4 expression and thus abated E2F-4 binding to MAT2A promoter at a site around -2779 bp, leading to an increase in the MAT2A promoter activity. These data might shed more light on the mechanisms responsible for liver fibrogenesis in obese patients with hyperleptinaemia.
大多数肥胖患者会出现高瘦素血症。瘦素主要由脂肪细胞产生，在肝纤维化中表现出促进作用。肝星状细胞（HSC）激活是肝纤维化发生的关键步骤，需要基因表达的全面重编程。DNA 甲基化的重塑是基因表达表观遗传调控的一种机制。S-腺苷甲硫氨酸（一种主要的生物甲基供体）的生物合成由诸如 MATⅡ的蛋氨酸腺苷转移酶（MAT）催化，已证明 MATⅡ在体外促进 HSC 激活。本研究主要旨在确定瘦素对 HSCs 中 MAT2A 表达（MATⅡ的催化亚基）的影响。结果表明，MAT2A 敲低减少了瘦素诱导的 HSC 激活和瘦素缺乏小鼠模型中的肝纤维化。瘦素促进了 HSCs 中 MAT2A 的表达，并增加了 MAT2A 启动子活性。β-连环蛋白途径/E2F-4 轴介导了瘦素对 MAT2A 表达的影响。瘦素诱导的 β-连环蛋白信号降低了 E2F-4 的表达，从而减少了 E2F-4 在 -2779bp 左右的 MAT2A 启动子上的结合，导致 MAT2A 启动子活性增加。这些数据可能为肥胖伴高瘦素血症患者肝纤维化的发生机制提供更多线索。
