The cAMP Responsive Element Binding Protein H Links Metabolic Inflammation with Hyperlipidemia in Hepatic Insulin Resistance

Insulin resistant is commonly associated with both increased circulating levels of tumor necrosis factor-alpha (TNF-alpha) and hepatic overproduction of very low density lipoproteins (VLDL). The cAMP responsive binding protein H (CREBH) is a transcription factor whose expression is induced by proinflammatory cytokines. In this study, our objective was to investigate the role of CREBH in mediating lipogenic diet induced hyperlipoproteinemia in the insulin resistance rodent models. By using the wild type and CREBH-null mouse models combined with fatty acid gavage and TNF-alpha treatment, we demonstrated that depletion of CREBH reduced both mRNA and protein expression of apolipoprotein B (apoB), a key structure protein in VLDL particle. In vitro, transient expression of CREBH cDNAs in McA cells induced significant increase of apoB mRNA and protein expression and VLDL secretion which indicated the positive regulatory impact of CREBH on apoB biosynthesis. Furthermore, treating McA cells with TNF-alpha activate...