FABP1: A NOVEL HEPATIC ENDOCANNABINOID AND CANNABINOID BINDING PROTEIN.

Endocannabinoids (EC) and cannabinoids are very lipophilic molecules requiring the presence of cytosolic binding proteins that chaperone these molecules to intracellular targets. While three different fatty acid binding proteins (FABP3, 5, 7) serve this function in brain, relatively little is known about how such hydrophobic EC and cannabinoids are transported within the liver. The most prominent hepatic FABP, liver fatty acid binding protein (FABP1, L-FABP), has high affinity for arachidonic acid (ARA) and ARA-CoA-suggesting that FABP1 may also bind ARA-derived EC (AEA, 2-AG). Indeed, FABP1 bound EC with high affinity as shown by displacement of FABP1-bound fluorescent ligands and by quenching of FABP1 intrinsic tyrosine fluorescence. FABP1 also had high affinity for most non-ARA containing EC, FABP1 inhibitors, EC uptake/hydrolysis inhibitors, phytocannabinoids, and less so synthetic cannabinoidreceptor (CB) agonists and antagonists. Physiological impact was examined with liver from wild-type (WT) versus FABP1 gene ablated (LKO) male mice. As shown by LC/MS, FABP1 gene ablation significantly increased hepatic levels of AEA, 2-AG, and 2-OG. These increases were not due to increased protein levels of EC synthetic enzymes (NAPEPLD, DAGL) or decreased level of EC degradative enzyme (FAAH), but correlated with complete loss of FABP1, decreased SCP2 (8-fold less prevalent than FABP1, but also binds ECs), and decreased degradative enzymes (NAAA, MAGL). These data indicated that FABP1 is not only the most prominent endocannabinoid and cannabinoid binding protein, but also impacts hepatic endocannabinoid levels.