title: Structural and functional interaction of fatty acids with human liver fatty acid-binding protein (L-FABP) T94A variant.
abstract: The human liver fatty acid-binding protein (L-FABP) T94A variant, the most common in the FABP family, has been associated with elevated liver triglyceride levels. How this amino acid substitution elicits these effects is not known. This issue was addressed using human recombinant wild-type (WT) and T94A variant L-FABP proteins as well as cultured primary human hepatocytes expressing the respective proteins (genotyped as TT, TC and CC). The T94A substitution did not alter or only slightly altered L-FABP binding affinities for saturated, monounsaturated or polyunsaturated long chain fatty acids, nor did it change the affinity for intermediates of triglyceride synthesis. Nevertheless, the T94A substitution markedly altered the secondary structural response of L-FABP induced by binding long chain fatty acids or intermediates of triglyceride synthesis. Finally, the T94A substitution markedly decreased the levels of induction of peroxisome proliferator-activated receptor α-regulated proteins such as L-FABP, fatty acid transport protein 5 and peroxisome proliferator-activated receptor α itself meditated by the polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid in cultured primary human hepatocytes. Thus, although the T94A substitution did not alter the affinity of human L-FABP for long chain fatty acids, it significantly altered human L-FABP structure and stability, as well as the conformational and functional response to these ligands.
authors.affiliation: Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Huang
authors.forename: Avery L
authors.initials: AL
authors.lastname: McIntosh
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Martin
authors.forename: Kerstin K
authors.initials: KK
authors.lastname: Landrock
authors.forename: Danilo
authors.initials: D
authors.lastname: Landrock
authors.forename: Shipra
authors.initials: S
authors.lastname: Gupta
authors.forename: Barbara P
authors.initials: BP
authors.lastname: Atshaves
authors.forename: Ann B
authors.initials: AB
authors.lastname: Kier
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Schroeder
mesh_terms: D000817:Anilino Naphthalenesulfonates; D000818:Animals; D015153:Blotting, Western; D002942:Circular Dichroism; D004591:Electrophoresis, Polyacrylamide Gel; D050556:Fatty Acid-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D014280:Triglycerides / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000817:Anilino Naphthalenesulfonates; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D011994:Recombinant Proteins; D014280:Triglycerides; C027132:1-anilino-8-naphthalenesulfonate
keywords: L-FABP; PUFA; TG; fatty acids; liver