Adipose tissue lipolysis and alcoholic fatty liver Project Summary Alcoholic fatty liver is one of the earliest pathological changes in the progression of alcoholic liver disease. Accumulation of lipid in the hepatocyte makes the liver susceptible to inflammatory mediators or other toxic agents, leading to further progression to hepatitis and eventually fibrosis. Therefore, lipid accumulation is one of the most fundamental cellular disorders in alcoholic liver disease, and reduction of liver fat would likely halt or slow the progression of alcoholic liver disease. While alcohol induces fat accumulation in the liver, a significant decrease in fat mass (lipoatrophy) has been documented in chronic alcoholism. Our preliminary studies demonstrated a negative correlation between adipose tissue mass and liver fat in mice chronically fed alcohol. We also found that attenuation of alcoholic fatty liver by zinc supplementation is accompanied by partial reversal of lipoatrophy, suggesting a link between lipoatrophy and alcoholic fatty liver. Our recent studies further demonstrated that alcohol exposure upregulated hepatic fatty acid transporter 5 (FATP5) and CD36 (also named fatty acid translocase), suggesting an increased fatty acid uptake in the liver. On the other hand, chronic alcohol exposure activated both hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) pathways in the adipose tissue, indicating an upregulation of lipolysis. Our overall hypothesis is that reverse fatty acid transport due to excess lipolysis of the adipose tissue plays a crucial role in pathogenesis of alcoholic fatty liver. To test this hypothesis, four specific aims are proposed.
Aim 1 is to determine if increased fatty acid uptake plays a crucial role in the development of alcoholic fatty liver. We will first document alcohol- induced increase in hepatic fatty acid uptake. We will then determine if blocking fatty acid uptake leads to reduction of alcoholic fatty liver.
Aim 2 is to determine if excess lipolysis of the adipose tissue is a causal factor in alcohol-increased hepatic fatty acid uptake. We will first determine if alcohol exposure can enhance hepatic deposition of fatty acids mobilized from adipose tissue. We will then determine if blocking adipose tissue fatty acid mobilization can lead to attenuation of alcoholic fatty liver.
Aim 3 is to investigate the molecular mechanisms by which alcohol induces excess lipolysis of the adipose tissue. We will first determine how alcohol exposure affects the lipolytic pathways in the adipose tissue. We will then define the role of nicotinic acid deficiency in HSL activation and the role of glucocorticoid in activation of ATGL lipolytic pathway.
Aim 4 is to define the role of zinc in the regulation of adipose tissue lipolysis. We will first determine the effects of dietary zinc on lipolytic pathways and nicotinic acid metabolism and glucocorticoid production. We will then determine how zinc affects lipolytic signaling transduction in the adipocytes.
Alcoholic fatty liver is the earliest pathological change in the progression of alcoholic liver disease, but the mechanisms by which alcohol causes hepatic lipid accumulation have not been well defined. Clinical studies have shown a significant decrease in fat mass in patients with alcoholic fatty liver. Our preliminary studies demonstrated a negative correlation between liver fat and adipose tissue mass. We also found that alcohol exposure stimulates adipose tissue lipolysis and hepatic fatty acid uptake. This project will test our hypothesis that reverse fatty acid transport due to excess lipolysis of the adipose tissue plays a crucial role in the pathogenesis of alcoholic fatty liver.
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