Berberine decreases plasma triglyceride levels and upregulates hepatic TRIB1 in LDLR wild type mice and in LDLR deficient mice

Abstract

AbstractTRIB1is a GWAS locus associated with plasma cholesterol and triglycerides (TG) levels. In mice, liver-specific overexpression of TRIB1 lowers plasma lipid levels. Berberine (BBR) is a natural lipid lowering drug that reduces plasma LDL-cholesterol (LDL-C), total cholesterol (TC) and TG in hyperlipidemic patients and in mice by mechanisms involving upregulation of hepatic LDL receptor (LDLR). Here, we demonstrated that BBR treatment reduced plasma LDL-C, TC and TG in LDLR wildtype (WT) mice fed a high fat and high cholesterol diet and it only lowered TG in LDLR WT mice fed a normal chow diet. In hypercholesterolemic LDLR deficient mice (Ldlr−/−), BBR treatment reduced plasma TG levels by 51% compared to the vehicle control without affecting plasma cholesterol levels. Hepatic gene expression analysis revealed thatTrib1mRNA levels were significantly elevated by BBR treatment in all three mouse models and increases ofTrib1mRNA expression were associated with reduced expression of lipogenic genes includingCebpa,Acc1andScd1.In vitrostudies further demonstrate that BBR inducesTRIB1mRNA expression by a transcriptional mechanism via ERK signaling pathway. These new findings warrant futurein vivostudies to determine the causal role of Trib1 in BBR-mediated TG lowering independent of LDLR regulation.