Liver disease is one of the leading causes of illness and death in the United States. Excessive alcohol consumption is a major risk factor for liver damage, and more than 2 million Americans suffer from liver disease caused by alcohol. Although hepatic steatosis is a prevalent phenotype among heavy alcohol drinkers, the mechanisms underlying its development are not well understood. It is currently thought that alcohol acts directly on the liver to alter lipid metabolism leading to development of hepatic steatosis. Our lab has recently delineated a novel brain-liver circuit in regulation of non-alcoholc fatty liver under physiologic conditions such as starvation and obesity. We show that hypothalamic neuropeptide Agouti-related protein (AGRP) acts in the brain to suppress hepatic sympathetic activity and to stimulate lipid synthesis. AGRP is required for the development of hepatic steatosis that occurs in starvation and obesity. Intriguingly, ethanol administration stimulates Agrp expression in the mouse hypothalamus, and AGRP-deficient mice are resistant to development of ethanol-induced hepatic steatosis without alteration of feeding and body weight. The goal of this proposal is to test the hypothesis that ethanol induces hepatic steatosis, at least in part, by stimulation of hypothalamic Agrp expression, resulting in alteration of hepati sympathetic activity and development of hepatic steatosis. Signaling mechanisms underlying alcohol's effects on Agrp expression and hepatic steatosis will be determined. We will further investigate the importance of modulating hepatic sympathetic activity in ethanol-induced hepatic steatosis. Finally, we will evaluate the therapeutic potentials of RNA-interference against Agrp in alleviating liver injury induced by chronic plus binge alcohol consumption. Taken together, experiments outlined in this proposal will define a new mechanism that underlies the etiology of ethanol- induced hepatic steatosis and will explore a novel strategy to treat alcoholic liver diseases.

Public Health Relevance

Alcohol abuse remains one of the common causes of acute and chronic liver disease, but there is no approved therapy by the Food and Drug Administration (FDA) for any stage of alcoholic liver disease. The goal of this proposal is to test the hypothesis that ethanol induces hepatic steatosis, at least in part, by stimulation of hypothalamic Agrp expression, leading to alteration of hepatic sympathetic activity and development of hepatic steatosis. Experiments outlined in this proposal will define a new mechanism that underlies the etiology of ethanol-induced hepatic steatosis and will explore a novel strategy to treat alcoholic liver diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01AA022665-01A1
Application #
8761674
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Brooks, Pj
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143