CREBH mediates metabolic inflammation to hepatic VLDL overproduction and hyperlipoproteinemia.

Metabolic inflammation is closely associated with hyperlipidemia and cardiovascular disease. However, the underlying mechanisms are not fully understood. The current study established that cAMP-responsive-element-binding protein H (CREBH), an acute-phase transcription factor, enhances very-low-density lipoprotein (VLDL) assembly and secretion by upregulating apolipoprotein B (apoB) expression and contributes to metabolic inflammation-associated hyperlipoproteinemia induced by TNFα, lipopolysaccharides (LPS), and high-fat diet (HFD) in mice. Specifically, overexpression of CREBH significantly induced mRNA and protein expression of apoB in McA-7777 cells. Luciferase assay further revealed that the presence of CREBH could significantly increase the activity of the apoB gene promoter. In contrast, genetic depletion of CREBH in mice resulted in significant reduction in expression of hepatic apoB mRNA. Challenging mice with an acute fat load led to upregulation of triglyceride (TG)-rich lipoprotein secretion in wild type mice, but not in CREBH-null mice. TNFα treatment activated hepatic CREBH expression, which in turn enhanced hepatic apoB biosynthesis and VLDL secretion. Metabolic inflammation induced by LPS or HFD also resulted in overproduction of apoB and hyperlipoproteinemia in wild type mice, but not in CREBH-null mice. This study demonstrates that CREBH could be a mediator between metabolic inflammation and hepatic VLDL overproduction in chronic metabolic disorders. This novel finding establishes CREBH as the first transcription factor that regulates apoB expression on the transcriptional level and the subsequent VLDL biosynthesis in response to metabolic inflammation. The study also provides novel insight into the pathogenesis of hyperlipidemia in metabolic syndrome.

KEY MESSAGES: CREBH mediates inflammatory signaling to VLDL overproduction in metabolic stress. Activation of CREBH in inflammation enhances mRNA and protein expression of apoB. CREBH presents a potential novel therapeutic target for hyperlipoproteinemia.