Hepatic response to ethanol feeding in a hepatocyte-specific fatty acid binding protein-4 knock out mouse model.

BACKGROUND: Early alcohol-dependent liver disease (ALD) is characterized by increased hepatic fat storage (hepatosteatosis). Fatty acid binding protein 4 (FABP4), a protein not normally expressed in liver, becomes highly expressed in ALD. This study developed a hepatocyte-specific FABP4 mouse knockout (HS-Fabp4(-/-)) to study liver responses to alcohol. METHODS: An HS-Fabp4(-/-) mouse was created using a Cre/loxP embryonic stem cell approach. Male and female HS-Fabp4(-/-) and wildtype (WT; C57Bl/6) mice were maintained on ethanol-drinking water (EtOH-DW) for 4-weeks. Liver damage, triglyceride content and pathology were assessed. Hepatic FABP1-9 mRNA and FABP4 and FABP5 protein were measured. Human hepatoma cell proliferation in response to exogenous FABP4 or FABP5 was analyzed. RESULTS: Hepatocyte-specific FABP4 deletion was confirmed in HS-Fabp4(-/-) mice. No gross phenotypic differences were observed between HS-Fabp4(-/-) and WT. Maintenance on EtOH-DW resulted in microsteatosis, increased hepatic triglycerides, and elevated aspartate and alanine transaminases, with no differences detected between pair-matched HS-Fabp4(-/-) and WT mice. Hepatic FABP1-9 mRNA analysis revealed increased FABP4 and FABP5 mRNA expression in WT mice, and elevated FABP5 mRNA in HS-Fabp4(-/-) mice in response to EtOH-DW, effects that were mirrored in serum FABP4/5 protein. Exposure of hepatoma cells to FABP4 or FABP5 revealed FABP4, but not FABP5, stimulated cell proliferation. CONCLUSIONS: Hepatocyte-specific FABP4 deletion does not alter hepatic fat accumulation in response to EtOH feeding. Hepatic FABP4 protein produced in response to EtOH is released from hepatocytes and exogenous FABP4 promotes hepatoma cell proliferation in vitro, an effect not observed for FABP5.