Significance: The proposed research is highly significant because instead of the current dogma that alcoholic hepatosteatosis is exclusively due to liver pathology, our novel hypothesis proposes the following complex interactions of adipose tissue, brain and liver: 1. Alcohol leads to increased expression and secretion of the adipokine, leptin in response to which hypothalamus over-expresses the leptin antagonists, the SOCS3 and PTP1B causing leptin resistance. 2. Alcohol-induced over-expressions of neuronal SOCS3 and PTP1B down regulate hepatic PGC11 and lipid oxidizing genes and up regulate PGC12, SREBP1c and lipogenic genes presumably via the relative decrease in SIRT1 and increase in HAT expressions. 3. Furthermore, the inability of leptin to activate AMPK to P04AMPK preserves the active form of ACC, the key enzyme of lipogenic pathway leading to increased lipogenesis. Simultaneously, the active ACC generates more malonyl CoA, a potent inhibitor of CPT1, the rate limiting enzyme of fatty acid oxidation pathway causing decreased lipid oxidation. Thus, alcohol-induced imbalance in brain-adipose axis feedback is responsible for alcoholic hepatosteatosis. Innovation: This application is innovative because of the following reasons: 1. We may discover that alcoholic liver injury is a complex pathogenic process in which the potential integrated actions of increased leptin from adipose tissue leads to hypothalamic over-expression of SOCS3 and PTP1B that adversely affect hepatic lipid oxidizing and lipogenic genes resulting in steatohepatitis. 2. There is a good potential for identifying a novel role for hypothalamic SOCS3 and/or PTP1B in causing alcoholic liver injury. and 3. We may show a novel way by which aberrations in hypothalamic adipose tissue feed-back axis has an impact on alcoholic liver injury. We provide the following data In support of our novel concepts though not in our mouse models: 1. Alcohol increases plasma leptin. 2. Neuronal SOCS3 KO and PTP1B KO mice do not accumulate liver fat even on a high fat diet. 3. Alcohol up regulates hepatic PGC12 and SREBP1c resulting in increased lipid synthesis. 4. Alcohol down regulates hepatic SIRT1 and PGC11 resulting in decreased lipid oxidation. 5. Alcohol up regulates ACC- and down regulates CPT1-mRNA expressions. 6. Alcohol decreases PO4 AMPK and increases acetylSREBP1c.
Specific Aims : Our two aims to address the complex action of alcohol are:
Aim 1. Does chronic ethanol up regulate adipose leptin mRNA/protein and plasma leptin with concomitant increase in hypothalamic SOCS3/ PTP1B mRNAs and their corresponding proteins in wild-type mice? Aim 2. Are neuronal SOCS3 KO and/or PTP1B KO mice protected from chronic alcoholic hepatosteatosis? If so, do the underlying mechanisms involve down regulation of PGC12, SREBP1c, and ACC and/or up regulation of SIRT1, PGC11, and CPT1? Reemphasis of Proposal's Innovation: The novelty of this proposal aims to show that alcohol-induced interactions of brain SOCS3/PTP1B-adipose-leptin axis feedback adversely affect hepatic lipid oxidizing and lipogenic genes leading to alcoholic hepatosteatosis. This may lead to novel therapeutic approaches.

Public Health Relevance

We propose to delineate the possible mechanism/s of how the pathogenesis of alcoholic hepatosteatosis involves a complex series of interactions between adipose tissue and brain adversely affect hepatic fat oxidizing and fat synthesizing genes. This may lead to novel therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AA020209-02
Application #
8144479
Study Section
Special Emphasis Panel (ZAA1-JJ (01))
Program Officer
Radaeva, Svetlana
Project Start
2010-09-20
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$151,389
Indirect Cost
Name
George Washington University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052