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

Miaoyun Zhao, Qiaozhu Su

Research output: Contribution to journalMeeting abstract

Abstract

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 activated CREBH and increased apoB protein level. Challenging the CREBH-null mice with a dose of long chain fatty acid through gavage or TNF-alpha treatment failed to stimulate apoB expression and the subsequent VLDL secretion which resulted in hepatic steatosis. Insulin treatment synergized the effect of CREBH on VLDL secretion which may be a contributing factor in insulin resistance induced hyperlipidemia. In conclusion, these data demonstrated that CREBH is the molecular link that mediates inflammatory cytokine signaling to overproduction of VLDL in hepatic insulin resistance. This novel finding provides new mechanistic insight in inflammatory cytokine induced hyperlipidemia in metabolic diseases
Original languageEnglish
Pages (from-to)393.7
Number of pages1
JournalThe FASEB Journal
Volume29
Issue numberNo. 1_supplement
Publication statusPublished - 01 Apr 2015

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