Fatty Acid Binding Protein‐1 (FABP1) and the Human FABP1 T94A Variant: Roles in the Endocannabinoid System and Dyslipidemias

Abstract

The first discovered member of the mammalian FABP family, liver fatty acid binding protein (FABP1, L-FABP), occurs at high cytosolic concentration in liver, intestine and in the case of humans also in kidney. While the rat FABP1 is well studied, the extent these findings translate to human FABP1 is not clear—especially in view of recent studies showing that endocannabinoids and cannabinoids represent novel rat FABP1 ligands and FABP1 gene ablation impacts the hepatic endocannabinoid system, known to be involved in non-alcoholic fatty liver (NAFLD) development. Although not detectable in brain, FABP1 ablation nevertheless also impacts brain endocannabinoids. Despite overall tertiary structure similarity, human FABP1 differs significantly from rat FABP1 in secondary structure, much larger ligand binding cavity, and affinities/specificities for some ligands. Moreover, while both mouse and human FABP1 mediate ligand induction of peroxisome proliferator activated receptor-α, (PPARα), they differ markedly in pattern of genes induced. This is critically important because a highly prevalent human SNP (26–38% minor allele frequency and 8.3±1.9% homozygous) results in a FABP1 T94A substitution that further accentuates these species differences. The human FABP1 T94A variant is associated with altered body mass index (BMI), clinical dyslipidemias (elevated plasma triglycerides and LDL cholesterol), atherothrombotic cerebral infarction, and non-alcoholic fatty liver disease (NAFLD). Resolving human FABP1 and the T94A variant’s impact on the endocannabinoid and cannabinoid system is an exciting challenge due to the importance of this system on hepatic lipid accumulation as well as behavior, pain, inflammation, and satiety.

Δ9-Tetrahydrocannabinol induces endocannabinoid accumulation in mouse hepatocytes: antagonism by Fabp1 gene ablation

“…However, nothing is known regarding the impact of Δ human NAFLD (24), especially in human subjects expressing the highly prevalent FABP1 T94A variant (26-38% minor allele frequency; 8.3±1.9% homozygous) (rev. in (21). While the human FABP1 T94A variant protein differs only modestly from its wild-type FABP counterpart in affinities for endocannabinoids (AEA, 2-AG) (25) as well as a variety of other ligands (26)(27)(28)(29), the conformation of FABP1 T94A variant is much less responsive to ligand-induced change (25,26) which in turn diminishes its ability to enter nuclei, interaction with, and activation of peroxisome proliferator activated receptor- (PPAR) therein (29).…”

“…Liver fatty acid binding protein (FABP1) has high affinity for the endogenous CB1 receptor agonist 2-AG (19)(20)(21). Therefore, the impact of 2-AG and/or FABP1 on hepatocyte level of AEA was examined in cultured primary hepatocytes from wild-type WT and Fabp1 gene ablated (LKO) mice.…”

Efectos del consumo de marihuana en adultos sobre la ingesta y el metabolismo de los nutrientes: una revisión

“…Partiendo de la revisión realizada, se describieron los diferentes mecanismos mediante los cuales el consumo de marihuana y la activación del sistema cannabinoide tienen producción de enzimas lipogénicas como ácido graso sintasa, de los niveles internos de ácidos grasos, producción de lipoproteínas VLDL, LDL y disminución en la producción de HDL, lo que finalmente se traduce en un aumento de niveles séricos de colesterol y triglicéridos 13,17,34 .…”

“…Se genera una hipertrofia de los adipocitos mediada por el receptor activado por proliferadores peroxisomales (PPARγ), involucrado en el proceso de diferenciación de los adipocitos y en la captación de glucosa tras el aumento de la sensibilidad a la insulina, proceso en el cual también se conoce la participación de dicho receptor 34,36,37 . De manera que se favorece la generación de grasa a nivel del hígado y su acumulación en el tejido adiposo 9,17,38,39 .…”

“…En cuanto a procesos como la lipólisis, la activación del sistema cannabinoide bloquea los mecanismos necesarios para el uso de los lípidos como sustrato energético a nivel de los adipocitos 13,16,17 , además de aumentar la expresión de PPARγ, el cual favorece la proliferación de los adipocitos y su hipertrofia [34][35][36] . Lo anterior puede propiciar la reserva de energía en forma de grasa y bloquear su gasto.…”