FABP‐1 gene ablation impacts brain endocannabinoid system in male mice

Abstract

Liver fatty acid binding protein (FABP1, L-FABP) has high affinity for and enhances uptake of arachidonic acid (ARA, C20:4, n-6) which, when esterified to phospholipids, is the requisite precursor for synthesis of endocannabinoids (EC) such as arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). The brain derives most of its ARA from plasma, taking up ARA and transporting it intracellularly via cytosolic fatty acid binding proteins (FABPs 3,5, and 7) localized within the brain. In contrast, the much more prevalent cytosolic FABP1 is not detectable in the brain but is instead highly expressed in the liver. Therefore, the possibility that FABP1 outside the central nervous system may regulate brain AEA and 2-AG was examined in wild-type (WT) and FABP1 null (LKO) male mice. LKO increased brain levels of AA-containing EC (AEA, 2-AG), correlating with increased free and total ARA in brain and serum. LKO also increased brain levels of non-ARA that contain potentiating endocannabinoids (EC*) such as OEA, PEA, 2-OG, and 2-PG. Concomitantly, LKO decreased serum total ARA-containing EC, but not non-ARA endocannabinoids. LKO did not elicit these changes in the brain EC and EC* due to compensatory upregulation of brain protein levels of enzymes in EC synthesis (NAPEPLD, DAGLα) or cytosolic EC chaperone proteins (FABPs 3, 5, 7, SCP-2, HSP70), or cannabinoid receptors (CB1, TRVP1). These data show for the first time that the non-CNS fatty acid binding protein FABP1 markedly affected brain levels of both ARA-containing endocannabinoids (AEA, 2-AG) as well as their non-ARA potentiating endocannabinoids.

FABP1: A Novel Hepatic Endocannabinoid and Cannabinoid Binding Protein

“…Fifth, loss of FABP1 markedly increased ARA-containing endocannabinoid (AEA, 2-AG) levels in liver (shown herein) and brain (13) of male mice. Despite similar endpoint, however, these increases were likely due to somewhat different mechanisms since FABP1 is not found in brain (11–13,53).…”

“…FABP1 bound AEA and 2-AG ≥3-fold more strongly as compared to SCP2 (13). In fact, FABP1 bound AEA and 2-AG with the highest affinity yet reported for any FABP family member.…”

“…For example, FABP1 gene ablation inhibits uptake of other fatty acids by cultured primary hepatocytes and in vivo (14–16) while FABP1 overexpression enhances uptake of such fatty acids as well as ARA (17–20). This would suggest that FABP1 gene ablation would decrease hepatic ARA uptake and availability for synthesis of AEA and 2-AG, opposite to the increased AEA and 2-AG observed in brain of FABP1 gene ablated male mice (13). On the other hand, it may be postulated that FABP1 will also binds these ECs to enhance their cytosolic trafficking for enzymatic degradation—analogous to the impact of ablating/inhibiting FABPs found in brain (7–10).…”

“…Importantly, pharmacological inhibition or ablation of these FABPs found in brain inhibits EC degradation, thereby enhancing EC accumulation and physiological action in brain (7–10). Surprisingly, although the liver form of fatty acid binding protein (FABP1) is not detectable in brain (11–13), nevertheless ablation of FABP1 markedly increases brain EC levels—especially AEA and 2-AG (13). The proposed mechanism whereby FABP1 gene ablation increases brain AEA and 2-AG levels is by its ability to bind ARA such that loss of FABP1 decreases hepatic ARA clearance, increases serum ARA availability for brain uptake, and increases brain ARA substrate for brain synthesis of AEA and 2-AG (13).…”

FABP1 knockdown in human enterocytes impairs proliferation and alters lipid metabolism

“…A direct comparison of Fabp2 −/− and Fabp1 −/− mice fed high fat diets also suggested that the two enterocyte proteins play different roles in intestinal and systemic metabolism [18]. Recent works indicate that Fabp1 −/− mice shows impaired endocannabinoid system both in liver and in the brain [23,24]. …”