Alcohol-induced liver disease (ALD) is a major health problem both in the US and worldwide. Fatty liver (steatosis) is the earliest and most common response of the liver to excessive ethanol consumption that predisposes the fatty liver to develop alcoholic steatohepatitis (ASH), hepatic fibrosis, cirrhosis and even hepatocellular carcinoma. Central among the many mechanisms proposed to play a role in the development of alcoholic hepatic steatosis is increased circulating fatty acids. Recent evidence suggests that alcohol-induced mobilization from adipose tissue is responsible for the increased circulating fatty acids and their enhanced hepatic uptake for subsequent fat accumulation. Insulin influences lipid metabolism throughout the body. Two of the important metabolic actions of insulin are to 1) promote the export of lipoproteins from the liver for storage in adipose tissue and 2) inhibit lipolysis in adipocytes. It is known that chronic ethanol exposure in rats disrupts insulin-dependent signal transduction thereby promoting lipolysis in adipocytes. In recent studies from our laboratory we found that chronic alcohol feeding, as expected, decreased plasma insulin levels. In addition, surprisingly, we also found increased plasma ghrelin levels in chronic alcohol-fed rats. Ghrelin, a hormone mainly secreted from stomach, inhibits insulin secretion from pancreatic ?-cells. Another protein known to be involved in insulin secretion is Rab3D, a small Ca2+-dependent Rab GTPase. Involvement of Rab3D is especially intriguing since we have recently reported that this protein is dramatically reduced in livers of ethanol-fed rats, and likely plays a role in altered protein trafficking in the alcohol-injured liver. Our preliminary data reported here shows that Rab3D is also decreased in pancreatic islets of ethanol-fed rats. On the basis of our preliminary data, and since insulin secretion has been shown to be significantly decreased in pancreatic islets of ethanol treated animals, we put forth the following hypothesis: Alcohol-induced increase in serum ghrelin levels and decrease in pancreatic Rab3D content both contribute to impaired insulin secretion from pancreatic ?-cells. Consequently, the reduced circulating insulin levels resulting from these alterations contribute to increased fatty acid mobilization from adipose tissue to liver, thereby exacerbating hepatic steatosis. We will utilize a variety of state-of-the art technologies to pursue novel and innovativ biological concepts that we have put forth in this application that include: one, alcohol administration elevates circulating ghrelin levels, resulting in impaired insulin secretion by pancreatic ?-cells; two, ethanol-associated lowering of Rab3D impairs insulin exocytosis in ?-cells; three, increased ghrelin and reduced insulin work together to modulate fat metabolism in liver and adipose tissue favoring hepatic steatosis, and four, antagonists of ghrelin could help attenuate alcohol-induced organ injury. Successful completion of these studies will provide new insights on the roles of the important players, ghrelin and Rab3D, in modulating the pancreas-adipose-liver axis after alcohol exposure.
The goal of this application is to examine the hypothesis that alcohol administration results in increased serum ghrelin levels and decreased pancreatic Rab3D content, both of which contribute to impaired insulin secretion from pancreatic ?-cells. These alterations result in increased fatty acid mobilization from adipose tissue to the liver, causing fatty liver disease. Successful completion of these studies will provide new insights on the roles of ghrelin and Rab3D under alcoholic conditions in modulating the pancreas-adipose-liver axis and favoring fat deposition in the liver.
