TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions

Abstract

Mammalian tribbles homolog 1 (TRIB1) regulates hepatic lipogenesis and is genetically associated with plasma triglyceride (TG) levels and cholesterol, but the molecular mechanisms remain obscure. We explored these mechanisms in mouse livers transfected with a TRIB1 overexpression, a shRNA template or a control (LacZ) adenovirus vector. The overexpression of TRIB1 reduced, whereas induction of the shRNA template increased, plasma glucose, TG, and cholesterolandsimultaneouslyhepatic TGandglycogen levels.The involvement of TRIB1 nhepatic lipid accumulation was supported by the findings of a human SNP association study. ATRIB1 SNP, rs6982502, was identified in an enhancer sequence, modulated enhancer activity in reporter gene assays, and was significantly (PZ9.39!10K7) associated with ultrasonographically diagnosed nonalcoholic fatty liver disease in a population of 5570 individuals. Transcriptome analyses of mouse livers revealed significant modulation of the gene sets involved in glycogenolysis and lipogenesis. Enforced TRIB1 expression abolished CCAAT/enhancer binding protein A (CEBPA), CEBPB, and MLXIPL proteins, whereas knockdown increased the protein level. Levels of TRIB1 expression simultaneously affected MKK4 (MAP2K4),MEK1 (MAP2K1), and ERK1/2 (MAPK1/3) protein levels andthephosphorylationof JNK, but not ofERK1/2.Pull-downandmammaliantwo-hybridanalyses revealed novel molecular interaction between TRIB1 and a hepatic lipogenic master regulator, MLXIPL. Co-expression of TRIB1 and CEBPAorMLXIPL reduced their protein levels and proteasome inhibitors attenuated the reduction. These data suggested that the modulation of TRIB1expression affects hepatic lipogenesis and glycogenesis through multiple molecular interactions. © 2014 Society for Endocrinology.