Role of Retinoids in the Regulation of Hepatic Glucose and Lipid Metabolism

The liver plays an important role in controlling glucose and lipid homeostasis. Metabolic abnormalities such as obesity and type 2 diabetes are often associated with profound changes in the expression of genes involved in hepatic glucose and lipid metabolism. Dietary nutrients provide us with macronutrients for energy and micronutrients for maintenance of general health. However, the effects of individual micronutrients on the development of metabolic diseases are unknown. Sterol regulatory element binding protein-1c (SREBP-1c) is the master regulator of fatty acid synthesis, and glucokinase (GK) is the key enzyme in glucose metabolism. Based on the preliminary results from our laboratory and others, we hypothesized that the metabolism of vitamin A (VA) regulate lipid and glucose metabolism by controlling the expression of Srebp-1c and Gck in hepatocytes. We show that retinoids synergize with insulin to induce the expression of Srebp-1c and Gck in primary rat hepatocytes. Retinoid-induced expression of Srebp-1c, due to the activation of RXR, results in increased expression of SREBP-1c target gene, Fas. Results obtained from the reporter gene assays demonstrate that the retinoic acid responsive elements (RAREs) in the Srebp-1c promoter overlap previously identified liver X receptor elements that mediate insulin action. For hepatic Gck, we first characterized its promoter and identified a RARE using serial deletion reporter gene assays and linker-scan analyses. This RARE overlaps a putative binding site for HNF4α [hepatic nuclear factor 4 alpha]. We then performed chromatin immunoprecipitation and electrophoretic mobility shift assays to study the binding of this RARE to nuclear receptors (NRs) potentially mediating retinoid actions: RARα [retinoic acid receptor alpha], RXRα [retinoid X receptor alpha], HNF4α, and COUP-TFII. We show that these NRs are capable of binding to the RARE and their binding activities are modulated by retinoic acid. In addition, the effects of the recombinant adenovirus-mediated over-expression of these NRs on the expression of retinoids- and insulin-responsive genes were analyzed in primary hepatocytes. We observed profound modulation of the gene expression by these NRs. We conclude that VA can control hepatic glucose and lipid metabolism via regulation of the expression of genes involved.