Hepatic Overexpression of Retinoic Acid Receptor ß Downregulates Mitochondrial Pyruvate Carrier 1 and Protects from Metabolic Dysregulation in ob/ob Mice

Our recent studies identify that retinoic acid receptor β (RARβ), a vitamin A-related nuclear receptor, regulates mitochondrial fatty acid oxidation in hepatocytes and in vivo in a fasting-inducible manner, which contributes to the metabolic adaptation to fasting. Mitochondrial pyruvate carrier (MPC) has been recently identified to control gluconeogenesis in hepatocytes, which contributes to the pathogenesis of diabetes. The present study aims to determine whether RARβ is linked to the control of glucose metabolism. We observed hepatic downregulation of RARβ occurred in high fat, high sucrose (HFHS) diet-fed mice and in genetically obese ob/ob mice. Treatment with all-trans-retinoic acid (RA), a natural ligand of RARβ and an approved drug for anticancer treatment, at doses of 2.5- 5.0 mg/kg/day for 4 weeks lowered fasting glucose levels and ameliorated glucose intolerance and insulin resistance in HFHS-fed mice, which was associated with increased hepatic gluconeogenic gene expression. Moreover, adenovirus-mediated overexpression of RARβ restored hepatic impairment of RARβ and systemic glucose intolerance and decreased hepatic gluconeogenesis by obesity. Mechanistically, overexpression of RARβ decreased obesity-induced expression of MPC1 and MPC2, key regulators of gluconeogenesis from pyruvate. Increasing RARβ in ob/ob mice also inhibited the induction of alanine transaminase (ALT), a key enzyme that converts alanine into pyruvate for glucose production. Moreover, overexpression of RARβ downregulated lipogenic gene expression, upregulated fatty acid oxidation, and improved hepatic steatosis and hyperlipidemia in ob/ob mice. Hepatic and systemic insulin resistance were also reduced by overexpressing RARβ. In sum, hepatic defective RARβ may contribute to the upregulation of MPC/ALT and gluconeogenesis in diabetes and RARβ can be a novel drug target to normalize metabolic dysregulation in diabetes.