Human Liver Fatty Acid Binding Protein-1 T94A Variant, Nonalcohol Fatty Liver Disease, and Hepatic Endocannabinoid...

Hepatic endocannabinoids (EC) and their major binding/"chaperone" protein (i.e., liver fatty acid binding protein-1 [FABP1]) are associated with development of nonalcoholic fatty liver (NAFLD) in animal models and humans. Since expression of the highly prevalent human FABP1 T94A variant induces serum lipid accumulation, it is important to determine its impact on hepatic lipid accumulation and the EC system. This issue was addressed in livers from human subjects expressing only wild-type (WT) FABP1 T94T (TT genotype) or T94A variant (TC or CC genotype). WT FABP1 males had lower total lipids (both neutral cholesteryl esters, triacylglycerols) and phospholipids than females. WT FABP1 males' lower lipids correlated with lower levels of the N-acylethanolamide DHEA and 2-monoacylglycerols (2-MAG) (2-OG, 2-PG). T94A expression in males increased the hepatic total lipids (triacylglycerol, cholesteryl ester), which is consistent with their higher level of CB1-potentiating 2-OG and lower antagonistic EPEA. In contrast, in females, T94A expression did not alter the total lipids, neutral lipids, or phospholipids, which is attributable to the higher cannabinoid receptor-1 (CB1) agonist arachidonoylethanolamide (AEA) and its CB1-potentiator OEA being largely offset by reduced potentiating 2-OG and increased antagonistic EPEA. Taken together, these findings indicate that T94A-induced alterations in the hepatic EC system contribute at least in part to the hepatic accumulation of lipids associated with NAFLD, especially in males.