Reduced insulin-mediated inhibition of VLDL secretion upon pharmacological activation of the liver X receptor in mice

The nuclear liver X receptor (LXR) regulates multiple aspects of cholesterol, triacylglycerol (TG), and carbohydrate metabolism. Activation of LXR induces the expression of genes encoding enzymes involved in de novo lipogenesis (DNL) resulting in hepatic steatosis in mice. Pharmacological LXR activation has also been reported to improve insulin sensitivity and glucose homeostasis in diabetic rodents. The effects of pharmacological LXR ligands on insulin's action on hepatic lipid metabolism are not known. We evaluated secretion of VLDL during a hyperinsulinemic euglycemic clamp in mice treated with the LXR-ligand T0901317. In untreated mice, hyperinsulinemia reduced the availability of plasma NEFA for VLDL-TG synthesis, increased the contribution of DNL to VLDL-TG, reduced VLDL particle size, and suppressed overall VLDL-TG production rate by approximately 50%. Upon T0901317 treatment, hyperinsulinemia failed to reduce VLDL particle size or suppress VLDL-TG production rate, but the contribution of DNL to VLDL-TG was increased. In conclusion, the effects of LXR activation by T0901317 on lipid metabolism can override the normal control of insulin to suppress VLDL particle secretion.