Abstract 337: Berberine Attenuates Hyperlipidemia in Mice by a Novel Underlying Mechanism Involving Trib1

Abstract

Recent genome wide association studies have identified tribbles homolog 1 (Trib1) as a risk factor in Myocardial Infarction. Trib1 has been shown to regulate VLDL production and hepatic lipogenesis in mice. Liver-specific overexpression of Trib1 reduced hepatic VLDL production and knockdown of Trib1 elevated plasma TG and cholesterol due to the increased VLDL production. However, currently little is known about the regulation of endogenous Trib1 expression and the relationship with plasma lipid homeostasis. In this study, we demonstrate that treating hyperlipidemic mice with 200 mg/kg of berberine (BBR), a natural lipid lowering compounds for 2 weeks reduced plasma total cholesterol by 24% and VLDL-cholesterol by 73% as compared to control mice. Hepatic gene expression analysis revealed that LDLR mRNA levels were not changed by BBR treatment. However, Trib1 mRNA levels were 70% (p<0.01) higher in BBR-treated group than that of control group. The elevation of hepatic Trib1 mRNA levels was also observed in BBR-treated mice fed a regular diet. To further characterize the LDLR-independent mechanism responsible for plasma TG lowering, BBR (150 mg/kg) was orally administered to LDLR knockout mice and we observed a 47% (p<0.05) reduction of serum TG levels after 6-days of BBR treatment while serum TC levels were not reduced. Importantly, the reduction of serum TG in LDLR KO mice by BBR treatment was accompanied by approximately 2-fold (p<0.05) increase in hepatic Trib1 mRNA levels in BBR-treated group as compared to control group. Furthermore, upregulation of Trib1 mRNA expression by BBR was inversely associated with the expression of key lipogenic genes (ACC1, SCD1, C/EBPα, GPAT1, MLXIPL and DGAT1) and measures of lipogenesis. By using HepG2 in vitro model system, we show BBR treatment also significantly increases Trib1 mRNA expression and reduces mRNA and protein expression of lipogenic genes. Taken together, our studies demonstrate for the first time that hepatic expression of Trib1 is upregulated by the natural lipid lowering compound BBR and that Trib1 plays an important role in the hypolipidemic effect of BBR independent of LDLR.