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FABP4 Released from Steatotic Hepatocytes in Alcoholic Liver Disease Enhances Hepatic Tumor Progression

Award Number: R21AA029241
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/25/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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FABP4 Released from Steatotic Hepatocytes in Alcoholic Liver Disease Enhances Hepatic Tumor Progression - SUMMARY Alcohol use disorders (AUDs) are significant clinical and financial healthcare burdens in the United States and globally. Within the spectrum of pathologies affected by AUDs, the central role of the liver in alcohol metabolism makes it particularly susceptible to damage. Alcoholic liver disease (ALD) arises from sustained, heavy alcohol ingestion and is characterized by a series of worsening liver pathologies (fat accumulation (hepatosteatosis), alcoholic hepatitis, fibrosis-cirrhosis). In ALD, hepatic cytochrome P450 2E1 is induced to metabolize ethanol leading to elevated intrahepatic acetaldehyde and oxidative stress, factors that increase the risk of genetic damage and development of hepatocellular carcinoma (HCC). Intracellular lipid movement and storage are closely regulated processes required to maintain liver and systemic homeostasis. In healthy individuals fatty acid binding proteins (FABPs) are expressed in a tissue- specific manner and function as critical chaperones during lipid sequestration and movement. In the healthy liver, FABP1 is the predominant FABP expressed in hepatocytes. Recent studies report FABP4 (an isoform usually expressed in adipocytes and macrophages) is synthesized and released by adipocytes to act as a paracrine- endocrine signaling molecule in specific disease states, including cancers arising in close proximity to adipose tissue. Studies by our group report FABP4 mRNA and protein expression is dramatically upregulated in hepatocytes isolated from alcohol-fed rodents, and following alcohol metabolism by CYP2E1-expressing HCC cells. These findings of increased FABP4 expression in ALD model systems are also evidenced in tissue and serum from ALD/ALD-HCC patients. Functionally, we report exogenous rhFABP4 stimulates ERK-MAPK and JNK signaling leading to HCC proliferation and migration in vitro. Collectively, these data have led us to hypothesize that “alcohol metabolism in ALD-induced steatotic hepatocytes leads to the induction of FABP4 synthesis and release which in turn stimulates HCC cell growth and migration”. Two Specific Aims are proposed; Aim 1 will determine the mechanism[s] by which hepatic alcohol metabolism induces FABP4 expression, and define the signaling mechanism[s] by which FABP4 regulates hepatoma cellfunction. To achieve this, we will combine knowledge derived from our Preliminary Data using established in vitro models with innovative proteomic approaches (Cell Signaling Phospho-Antibody Array) to accurately determine the signaling networks regulated by FABP4. Aim 2 will demonstrate the significance of FABP4 signaling in alcohol-dependent HCC expansion and progression in vivo. These studies will utilize a novel hepatocyte-specific FABP4-/- mouse (HS-FABP4-/-) and an orthotopic model of tumor progression. In parallel, we will expand our ongoing analyses of tissue and serum from ALD and ALD-HCC patients for FABP4 expression to determine the clinical relevance of altered FABP4 expression during ALD and HCC progression.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	THE CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY	1000 BLYTHE BLVD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Alcohol Research Programs	000	2	1/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $185,844 )
2022	2022	CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY, THE	1000 BLYTHE BOULEVARD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Alcohol Research Programs	000	2	8/12/2022	NON-COMPETING CONTINUATION	$185,844
														Subtotal = $185,844

Issue Date FY: 2021 ( Subtotal = $224,969 )
2021	2021	CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY, THE	1000 BLYTHE BOULEVARD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Alcohol Research Programs	000	1	9/20/2021	NEW	$224,969
														Subtotal = $224,969

Grand Total All Awards = $410,813

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FABP4 Released from Steatotic Hepatocytes in Alcoholic Liver Disease Enhances Hepatic Tumor Progression

Award Number: R21AA029241

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/25/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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