期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 24, 期 17, 页码 10063-10074出版社
WILEY
DOI: 10.1111/jcmm.15614
关键词
hepatic stellate cell; liver fibrosis; methionine adenosyltransferase; sterol regulatory element-binding protein 1c
资金
- National Natural Science Foundation of China [81570553]
Sterol regulatory element-binding protein 1c (SREBP1c) plays key roles in maintenance of hepatic stellate cell (HSC) quiescence. The present researches investigated the mechanisms underlying the effects of SREBP1c on HSCs and liver fibrogenesis by HSC-targeted overexpression of the active SREBP1c using adenovirus in vitro and in vivo. Results demonstrated that SREBP1c exerted inhibitory effects on TAA-induced liver fibrosis. SREBP1c down-regulated TGF beta 1 level in liver, reduced the receptors for TGF beta 1 and PDGF beta, and interrupted the signalling pathways of Smad3 and Akt1/2/3 but not ERK1/2 in HSCs. SREBP1c also led to the decreases in the protein levels of the bromodomain-containing chromatin-modifying factor bromodomain protein 4, methionine adenosyltransferase 2B (MAT2B) and TIMP1 in HSCs. In vivo activated HSCs did not express cyclin D1 and cyclin E1 but SREBP1c down-regulated both cyclins in vitro. SREBP1c elevated PPAR gamma and MMP1 protein levels in the model of liver fibrosis. The effect of SREBP1c on MAT2B expression was associated with its binding to MAT2B1 promoter. Taken together, the mechanisms underlying the effects of SREBP1c on HSC activation and liver fibrosis were involved in its influences on TGF beta 1 level, the receptors for TGF beta 1 and PDGF beta and their downstream signalling, and the molecules for epigenetic regulation of genes.
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