Activation of the sterol regulatory element-binding proteins (SREBPs), a step regulated by a cluster of ER-resident proteins, Insig-1, Insig-2 and SCAP, is rate limiting in hepatic de novo lipogenesis. We previously reported that feeding R-alpha-lipoic acid (LA) to ZDF (fa/fa) rats improves severe hypertriglyceridemia and lowers abdominal fat mass by inhibiting expression of genes involved in hepatic long-chain fatty acids and triacylglycerol syntheses. In this study, we characterized a novel mechanism of action of LA that explains its triacylglycerol lowering properties. Dietary LA activates liver specific transcription factor cAMP responsive element binding protein H (CREBH), which in turn enhances transcription and translation of Insig-1 and Insig-2. Chromatin immunoprecipitation (ChIP) assay demonstrated interaction between CREBH and the promoter of Insig-2 but not Insig-1. The increased abundance of Insig-1 and Insig-2 proteins contributes to sequester SREBP-1c and SREBP-2 in the ER and prevents their translocation to the Golgi apparatus where they would become activated. As a consequence, mRNA expression of genes involved in fatty acid and cholesterol synthesis, including FASN, ACC, SCD-1, HMGCR and LDL receptor, were significantly decreased in LA-fed animals versus pair-fed controls. Concomitantly, the assembly and secretion of very-low-density lipoproteins (VLDL) by primary hepatocytes were suppressed in the LA-fed ZDF rats as indicated by the decrease in VLDL-associated apolipoprotein B and apolipoprotein E. In vitro, treating a rat McA-RH7777 hepatoma cells with LA (200 micromole) activated CREBH, induced expression of Insig-1 and Insig-2, and hindered the palmitic acid-induced synthesis of triacylglycerol. This study provides new mechanistic insight into the triacylglycerol lowering properties of LA and supports the therapeutic potential of LA against hypertriglyceridemia.
Nobiletin enhances the development and quality of bovine embryos in vitro during two key periods of embryonic genome activation
