Alcoholic fatty liver is considered as the earliest pathological alteration of progression in alcoholic liver disease (ALD) from hepatic steatosis to hepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. Hepatic reverse transport of free fatty acids (FFAs) derived from adipose hyperlipolysis resulting from alcohol ingestion plays a critical role in fatty liver formation. However, the mechanisms by which alcohol regulates adipose tissue lipolysis are unclear. Recently, fibroblast growth factor 21 (FGF21) has emerged as a hepatic regulatory factor that acts on multiple targets, including the liver itself in an autocrine fashion, and importantly on white adipose tissue to regulate lipid homeostasis. We have found that FGF21 plays a critical role in alcohol-induced adipose lipolysis and in hepatic fat accumulation in animal models of ALD, and circulating FGF21 levels are significantly increased in patients with ALD and in experimental animal models. However, how FGF21 regulates adipose tissue lipolysis during alcohol exposure is not known.
The aims of this project are to investigate the role of FGF21 in adipose tissue lipolysis in response to alcohol exposure to improve our understanding of the molecular mechanisms in the regulation and action of this hormone in ALD, and to assess the therapeutic potential in alcohol-induced fatty liver formation. To achieve this goal, we will carry out the following specific aims.
In aim 1 we will determine whether FGF21 plays a stimulatory role in adipose tissue lipolysis and the underlying mechanisms associated with hormone sensitive lipase and perilipin pathway during alcohol exposure using FGF21 knockout and transgenic overexpression mouse models. In the second aim, we will test our hypothesis that adipose tissue specific disruption of FGF21 decreases FFA release and hepatic uptake and attenuates alcohol-induced fatty liver formation using adipose selective ?-klotho knockout mice.

Public Health Relevance

Alcoholic fatty liver is considered as the earliest pathological alteration of progression in alcoholic liver disease (ALD) from hepatic steatosis to hepatitis, fibrosis, cirrhosis and even hepatocellular carcinoma. Using animal models, we will investigate the role of FGF21 in response to alcohol exposure to improve our understanding of the molecular mechanisms in the regulation and action of this hormone in ALD, and to assess the therapeutic potential in alcohol- induced fatty liver formation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA022416-01A1
Application #
8702281
Study Section
Biomedical Research Review Subcommittee (AA)
Program Officer
Jung, Kathy
Project Start
2014-07-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40202
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