title: Human FABP1 T94A variant impacts fatty acid metabolism and PPAR-α activation in cultured human female hepatocytes.
abstract: Although human liver fatty acid-binding protein (FABP1) T94A variant has been associated with nonalcoholic fatty liver disease and reduced ability of fenofibrate to lower serum triglycerides (TG) to target levels, molecular events leading to this phenotype are poorly understood. Cultured primary hepatocytes from female human subjects expressing the FABP1 T94A variant exhibited increased neutral lipid (TG, cholesteryl ester) accumulation associated with (1) upregulation of total FABP1, a key protein stimulating mitochondrial glycerol-3-phosphate acyltransferase (GPAM), the rate-limiting enzyme in lipogenesis; (2) increased mRNA expression of key enzymes in lipogenesis (GPAM, LPIN2) in heterozygotes; (3) decreased mRNA expression of microsomal triglyceride transfer protein; (4) increased secretion of ApoB100 but not TG; (5) decreased long-chain fatty acid (LCFA) β-oxidation. TG accumulation was not due to any increase in LCFA uptake, de novo lipogenesis, or the alternate monoacylglycerol O-acyltransferase pathway in lipogenesis. Despite increased expression of total FABP1 mRNA and protein, fenofibrate-mediated FABP1 redistribution to nuclei and ligand-induced peroxisome proliferator-activated receptor (PPAR-α) transcription of LCFA β-oxidative enzymes (carnitine palmitoyltransferase 1A, carnitine palmitoyltransferase 2, and acyl-coenzyme A oxidase 1, palmitoyl) were attenuated in FABP1 T94A hepatocytes. Although the phenotype of FABP1 T94A variant human hepatocytes exhibits some similarities to that of FABP1-null or PPAR-α-null hepatocytes and mice, expression of FABP1 T94A variant did not abolish or reduce ligand binding. Thus the FABP1 T94A variant represents an altered/reduced function mutation resulting in TG accumulation.
authors.affiliation: Departments of Physiology and Pharmacology, and.
authors.forename: Avery L
authors.initials: AL
authors.lastname: McIntosh
authors.affiliation: Departments of Physiology and Pharmacology, and.
authors.forename: Huan
authors.initials: H
authors.lastname: Huang
authors.affiliation: Departments of Physiology and Pharmacology, and.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Storey
authors.affiliation: Pathobiology, Texas A & M University, College Station, Texas;
authors.forename: Kerstin K
authors.initials: KK
authors.lastname: Landrock
authors.affiliation: Pathobiology, Texas A & M University, College Station, Texas;
authors.forename: Danilo
authors.initials: D
authors.lastname: Landrock
authors.affiliation: Departments of Physiology and Pharmacology, and.
authors.forename: Anca D
authors.initials: AD
authors.lastname: Petrescu
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan.
authors.forename: Shipra
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan.
authors.forename: Barbara P
authors.initials: BP
authors.lastname: Atshaves
authors.affiliation: Pathobiology, Texas A & M University, College Station, Texas;
authors.forename: Ann B
authors.initials: AB
authors.lastname: Kier
authors.affiliation: Departments of Physiology and Pharmacology, and fschroeder@cvm.tamu.edu.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Schroeder
mesh_terms: D053299:Apolipoprotein B-100 / Q000378:metabolism; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D014644:Genetic Variation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D050155:Lipogenesis / Q000235:genetics; D008875:Middle Aged; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism
chemical_list: D053299:Apolipoprotein B-100; D002788:Cholesterol Esters; C493319:FABP1 protein, human; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D012333:RNA, Messenger; D014280:Triglycerides; D011345:Fenofibrate
keywords: fatty acid; fibrate; hepatocyte; liver fatty acid-binding protein; β-oxidation