Role of vitamin A status and its catabolism in the regulation of glucose and lipid homeostasis in rats under physiological and disease conditions

The increased number of individuals with metabolic diseases has become a public health concern. Vitamin A (VA, retinol) is required to maintain the general health of an individual. How VA contributes to the regulation of glucose and lipid homeostasis in normal and metabolic disease states is unclear. VA’s physiological activities are mainly mediated by its metabolite, retinoic acid (RA), which activates several transcriptional factors in the nuclear receptor super family and in turn, regulates the expression of numerous genes for macronutrient metabolism. For the RA production, retinol is first oxidized into retinal and then from retinal to RA. We hypothesize that VA status and dynamic production of RA play a role in the control of glucose and fatty acid metabolism. This dissertation summarized my investigation of VA’s role in metabolism: (1) We compared the expression levels of RA-producing enzymes in the liver of Zucker lean (ZL) and fatty (ZF) rats. We found that the hepatic expression levels of retinaldehyde dehydrogenase family 1 gene (Raldh1) mRNA and RALDH1 protein were higher in ZF rats than that in ZL rats. This elevated RALDH1 expression may cause the excessive RA production, which may enhance the hepatic lipogenesis and lead to the hepatic insulin resistance; (2) We compared the expression levels of insulin-regulated genes in the liver of VA deficient (VAD) and VA sufficient (VAS) ZL rats in response to the cycle of fasting and refeeding, a normal physiological condition. We observed that VA status and its dietary availability play a role in the expression levels of insulin-regulated gene in the rat liver; (3) We further used streptozotocin (STZ) to induce insulin-dependent diabetes mellitus in both VAD and VAS rats, a disease condition. The hepatic expression levels of insulin-regulated genes in these animals treated with control, RA, insulin and insulin + RA were investigated. The effects of VA status and RA production on the regulation of the hepatic gene expression were also observed. We conclude that VA status and dynamic RA production contribute to the expression of hepatic genes, which in turn regulate glucose and fatty acid homeostasis.