Grant Abstract: Hepatic retinoid metabolism and signaling in starvation and diabetes.

Grant Number: 5R01DK124921-04
PI Name: Kedishvili
Project Title: Hepatic retinoid metabolism and signaling in starvation and diabetes.

Abstract: Liver is the central metabolic hub that coordinates the carbohydrate and lipid metabolism. The bioactive derivative of vitamin A, retinoic acid (RA) was shown to regulate a number of major metabolic genes including phosphoenolpyruvate carboxykinase, fatty acid synthase, carnitine palmitoyltransferase 1, and glucokinase among others. Expression levels of these genes undergo profound changes during metabolic transitions such as adaptation to starvation, or in response to insufficient insulin signaling during type 1 diabetes. However, it is not known whether the levels of RA in liver change during such metabolic remodeling, and how the changes in RA levels, in turn, might affect the liver’s capacity for metabolic adaptation. To start addressing this fundamental gap in our knowledge, we have carried out preliminary studies targeting hepatic retinoid metabolism and signaling in the well-fed state, in starvation, and in type 1 diabetes. These initial studies have yielded several novel and paradigm-shifting observations. First of all, our preliminary data indicate that fed-to- starved transition is associated with significant downregulation of hepatic RA biosynthesis and signaling that stems from the downregulation of hepatic retinol dehydrogenase activity, which is the rate-limiting step in RA biosynthesis. Second, our preliminary studies suggest that the decrease in the overall hepatic retinol dehydrogenase activity is associated with changes in subcellular localization of retinol dehydrogenase 10 and a decrease in its overall cellular abundance. Third, our preliminary studies suggest that, in contrast to starvation, the untreated type 1 diabetes is associated with upregulation of RA biosynthesis and signaling. This upregulation of RA biosynthesis appears to come about as a result of an increase in hepatic retinol dehydrogenase activity, which, in turn, correlates with the increase in cellular abundance of RDH10 and changes in its subcellular localization. Taken together, our preliminary studies suggest that the downregulation of hepatic RA biosynthesis and signaling is critical for an orderly adaptation to starvation. In contrast, the upregulation of hepatic RA biosynthesis and signaling in type 1 diabetes might be a harmful outcome contributing to the metabolic inflexibility associated with this disease. Importantly, our initial findings suggest the existence of a novel, previously unrecognized mechanism by which the hepatic RA biosynthesis is regulated through adjustments in subcellular localization and cellular abundance of retinol dehydrogenase 10. In this application, we propose to examine these novel concepts through the following Specific Aims: 1) to characterize the hepatic retinoid metabolism and signaling in the well-fed state and in starvation; and 2) to investigate the hepatic retinoid metabolism and signaling in type 1 diabetes. The results of these studies will uncover the molecular mechanisms responsible for coordination of RA levels with metabolic status of liver and will lay the foundation for development of better informed therapies targeting metabolic disease. PUBLIC HEALTH RELEVANCE: In vitro assays suggest that Vitamin A derivative, retinoic acid, regulates numerous metabolic genes which undergo profound changes in expression levels during metabolic transitions such as adaptation to starvation, or in response to insufficient insulin signaling in type I diabetes. However, remarkably little is known about the fate of vitamin A metabolism and retinoic acid levels during such transitions. Based on our preliminary data, we propose to test a hypothesis that the rate of retinoic acid biosynthesis is carefully adjusted during metabolic transitions to enable proper remodeling of hepatic energy metabolism, while in type 1 diabetes this mechanism fails thereby exacerbating the disease.

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