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.
