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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA018844-06
Application #
8517436
Study Section
Special Emphasis Panel (ZAA1-JJ (06))
Program Officer
Gao, Peter
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$262,340
Indirect Cost
$74,283
Name
University of North Carolina Greensboro
Department
Nutrition
Type
Schools of Arts and Sciences
DUNS #
616152567
City
Greensboro
State
NC
Country
United States
Zip Code
27402
Zhang, Wenliang; Sun, Qian; Zhong, Wei et al. (2016) Hepatic Peroxisome Proliferator-Activated Receptor Gamma Signaling Contributes to Alcohol-Induced Hepatic Steatosis and Inflammation in Mice. Alcohol Clin Exp Res 40:988-99
Dong, Daoyin; Zhong, Wei; Sun, Qian et al. (2016) Oxidative products from alcohol metabolism differentially modulate pro-inflammatory cytokine expression in Kupffer cells and hepatocytes. Cytokine 85:109-19
Sun, Qian; Zhong, Wei; Zhang, Wenliang et al. (2016) Defect of mitochondrial respiratory chain is a mechanism of ROS overproduction in a rat model of alcoholic liver disease: role of zinc deficiency. Am J Physiol Gastrointest Liver Physiol 310:G205-14
Sun, Qian; Zhang, Wenliang; Zhong, Wei et al. (2016) Pharmacological inhibition of NOX4 ameliorates alcohol-induced liver injury in mice through improving oxidative stress and mitochondrial function. Biochim Biophys Acta 1861:2912-2921
Sun, Qian; Zhang, Wenliang; Zhong, Wei et al. (2016) Dietary Fisetin Supplementation Protects Against Alcohol-Induced Liver Injury in Mice. Alcohol Clin Exp Res 40:2076-2084
Berger, Paige K; Pollock, Norman K; Laing, Emma M et al. (2015) Zinc Supplementation Increases Procollagen Type 1 Amino-Terminal Propeptide in Premenarcheal Girls: A Randomized Controlled Trial. J Nutr 145:2699-704
Zhong, Wei; Zhang, Wenliang; Li, Qiong et al. (2015) Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice. J Hepatol 62:1375-81
Zhong, Wei; Li, Qiong; Zhang, Wenliang et al. (2015) Modulation of Intestinal Barrier and Bacterial Endotoxin Production Contributes to the Beneficial Effect of Nicotinic Acid on Alcohol-Induced Endotoxemia and Hepatic Inflammation in Rats. Biomolecules 5:2643-58
Sun, Qian; Zhong, Wei; Zhang, Wenliang et al. (2015) Zinc deficiency mediates alcohol-induced apoptotic cell death in the liver of rats through activating ER and mitochondrial cell death pathways. Am J Physiol Gastrointest Liver Physiol 308:G757-66
Zhong, Wei; Li, Qiong; Sun, Qian et al. (2015) Preventing Gut Leakiness and Endotoxemia Contributes to the Protective Effect of Zinc on Alcohol-Induced Steatohepatitis in Rats. J Nutr 145:2690-8

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