Hepatic VLDL production in ob/ob mice is not stimulated by massive de novo lipogenesis and is less sensitive to the suppressive effects of insulin

Hepatic VLDL production in ob/ob mice is not stimulated by massive de novo lipogenesis and is less sensitive to the suppressive effects of insulin Less suppression of VLDL production by insulin in ob/ob mice 66 ABSTRACT Type 2 diabetes mellitus in humans is associated with increased de novo lipogenesis (DNL), increased fatty acid (FA)-flux from peripheral tissues, decreased FA oxidation and hepatic steatosis. In type 2 diabetes mellitus, production of VLDL is increased and resistant to the suppressive effects of insulin. The relationships between FA metabolism, hepatic steatosis and VLDL production are incompletely understood. We investigated VLDL formation in relation to DNL and insulin sensitivity in female ob/ob mice, a model of type 2 diabetes with hepatic steatosis. Hepatic triglyceride (5-fold) and cholesteryl ester (15-fold) contents were increased in ob/ob mice compared to lean controls. Hepatic DNL was increased ~10-fold in ob/ob mice whereas hepatic cholesterol synthesis was not affected. Basal rates of hepatic VLDL-triglyceride and-apoB100 production were also similar between the groups. Hyperinsulinemic clamping reduced VLDL-triglyceride and-apoB100 production rate by ~60% and ~75%, respectively, in lean mice but only by ~20% and ~20%, respectively, in ob/ob mice. No difference in hepatic expression of genes encoding apolipoprotein B, microsomal triglyceride transfer protein and diacylglycerolacyltransferase-1 were found. Hepatic gene expression and protein phosphorylation of the insulin receptor and insulin receptor substrate-isoforms were reduced in ob/ob mice. Thus, strongly induced hepatic DNL is not associated with increased basal VLDL production in ob/ob mice, which might be related to differential hepatic zonation of apoB synthesis (periportal) and lipid accumulation (perivenous) and/or relatively low rates of cholesterogenesis. Insulin is unable to effectively suppress VLDL-triglyceride production in ob/ob mice, presumably due to impaired insulin signaling.