Abstract
BackgroundThe aim of this study was to investigate how the signaling pathway downstream of mTOR/S6K1 contributes to the regulation of SREBP-1c expression during lipogenesis in HepG2 cells.MethodsThe model of steatosis was established using human hepatocytes HepG2 and inducting them with sodium palmitate. mTOR, S6K1 and LXRα were inhibited by rapamycin, PF-4708671 and siRNA-LXRα, respectively. After a variety of different treatment, the levels of intracellular triglycerides, the accumulation of lipid droplets and the expression levels of related genes were detected.ResultsRapamycin, PF-4708671 and siRNA-LXRα treatment could decrease the accumulation of triglycerides and lipid droplets induced by sodium palmitate in HepG2 cells, and the inhibitory effect could be enhanced by the combination of them. Sodium palmitate stimulated the expression of genes encoding mTOR, S6K1, LXRα, SREBP-1c and SREBP-1c target enzymes (FAS and ACC1) in HepG2 cells. Moreover, these genes were sensitive to rapamycin. PF-4708671 also decreased the expression of these genes, except for the mTOR gene, and the extent of reduction could be enhanced by combination with rapamycin. Knockdown of LXRα decreased the expression of SREBP-1c, FAS and ACC1, but it had no effect on the expression of mTOR or S6K1. Furthermore, rapamycin and PF-4708671 enhanced the inhibitory effect of siRNA-LXRα.ConclusionsmTOR/S6K1 regulates the SREBP-1c signaling pathway through LXRα in sodium palmitate-induced HepG2 cells, suggesting LXRα might be a potential therapeutic target for NAFLD.
Highlights
The aim of this study was to investigate how the signaling pathway downstream of mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) contributes to the regulation of SREBP-1c expression during lipogenesis in HepG2 cells
Non-alcoholic fatty liver disease (NAFLD) pathogenesis is considered to be associated with the mammalian target of rapamycin signaling pathway [5].NAFLD is a manifestation of systemic insulin resistance, and mTOR and S6K1 are key components of the insulin signaling pathway [6, 7]. mTOR is a serine/threonine protein kinase that acts as an important molecular junction between nutrients and metabolic processes indispensable for cell growth
Sodium palmitate-induced lipid accumulation is associated with the increase in both mTOR/S6K1 and Liver X receptor-α (LXRα) levels via the upregulation of downstream lipogenic genes To elucidate the mechanism of action of sodium palmitate, the protein and mRNA expression levels of SREBP1c, a transcription factor that controls lipogenesis, and its target enzymes (FAS and ACC1) were examined using Western blotting and quantitative real-time PCR (qRT-PCR), respectively
Summary
The aim of this study was to investigate how the signaling pathway downstream of mTOR/S6K1 contributes to the regulation of SREBP-1c expression during lipogenesis in HepG2 cells. Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide. NAFLD is clinically defined by the accumulation of excess lipids, mainly in the form of triacylglycerol, exceeding 5-10% of the liver weight, in the absence of any primary cause (such as significant alcohol intake, viral hepatic infections, or other specific causes of liver disease) [1]. Patients with NAFLD tend to suffer from metabolic syndromes including obesity, type 2 diabetes mellitus and dyslipidemia [4].These data highlight the global importance of understanding NAFLD pathogenesis, which remains incompletely understood. MTOR is a serine/threonine protein kinase that acts as an important molecular junction between nutrients and metabolic processes indispensable for cell growth.
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