Human Liver Fatty Acid Binding Protein‐1 T94A Variant, Nonalcohol Fatty Liver Disease, and Hepatic Endocannabinoid System

Abstract

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.

Sterol Carrier Protein‐2/Sterol Carrier Protein‐x/Fatty Acid Binding Protein‐1 Ablation Impacts Response of Brain Endocannabinoid to High‐Fat Diet

“…Finally, mutations in the human Fabp1 gene are highly prevalent (>30% of human subjects carry the allele encoding for the FABP1 T94A variant) (Schroeder et al, ). While this substitution does not significantly affect ligand affinity, it markedly alters ligand‐induced conformational changes and the ability to function in FABP1‐mediated ligand activation of PPARα (Huang et al, , ; Martin et al, , , ; Schroeder et al, ). Together, these impairments adversely impact both the cardiovascular system (e.g.…”

Scp-2/Scp-x ablation in Fabp1 null mice differentially impacts hepatic endocannabinoid level depending on dietary fat

“…Conversely, liver FABP1 level is increased in both animal and human models of NAFLD [17, 18, 79]. In addition, expression of the highly common human FABP1 T94A variant is highly associated with NAFLD in human subjects [12, 80, 81].…”

Effect of liver fatty acid binding protein (L-FABP) gene ablation on lipid metabolism in high glucose diet (HGD) pair-fed mice

“…Elevated hepatic triacylglycerol (TG) is considered a hallmark of human non-alcoholic fatty liver disease (NAFLD), as determined primarily by magnetic resonance imaging (MRI) or by histology [1]. Relatively few studies have actually determined the hepatic lipid content or composition in NAFLD and determined actual levels of TG [2][3][4][5]. Fatty acids comprising hepatic TG are derived from two major sources.…”