Fatty Acid Binding Protein-1 (FABP1) and the Human FABP1 T94A Variant: Roles in the Endocannabinoid System and Dyslipidemias.
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 single nucleotide polymorphism (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 in hepatic lipid accumulation as well as behavior, pain, inflammation, and satiety.
Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA. fschroeder@cvm.tamu.edu.
Friedhelm
F
Schroeder
Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA.
Avery L
AL
McIntosh
Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA.
Gregory G
GG
Martin
Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA.
Huan
H
Huang
Department of Pathobiology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA.
Danilo
D
Landrock
Department of Pathobiology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA.
Sarah
S
Chung
Department of Pathobiology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA.
Kerstin K
KK
Landrock
Department of Biochemistry and Biophysics, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA.
Lawrence J
LJ
Dangott
Avanti Polar Lipids, 700 Industrial Park Dr., Alabaster, AL, 35007-9105, USA.
Shengrong
S
Li
Department of Anesthesiology, Stony Brook University, Stony Brook, NY, 11794, USA.
Martin
M
Kaczocha
Department of Pharmacology, Physiology, and Therapeutics and Chemistry, University of North Dakota, Grand Forks, ND, 58202-9037, USA.
Eric J
EJ
Murphy
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA.
Barbara P
BP
Atshaves
Department of Pathobiology, Texas A&M University, TVMC, College Station, TX, 77843-4466, USA.
Ann B
AB
Kier
D000818:Animals; D015992:Body Mass Index; D001921:Brain / Q000378:metabolism; D002544:Cerebral Infarction / Q000209:etiology / Q000235:genetics; D050171:Dyslipidemias / Q000235:genetics* / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism*; D050556:Fatty Acid-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics; D047493:PPAR alpha / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017433:Protein Structure, Secondary; D051381:Rats; D013045:Species Specificity
D063388:Endocannabinoids; C493319:FABP1 protein, human; C493320:Fabp1 protein, mouse; C493321:Fabp1 protein, rat; D050556:Fatty Acid-Binding Proteins; D047493:PPAR alpha
Fatty acid binding protein (FABP1); Liver; Triglyceride