Genetic and Structural Evaluation of Fatty Acid Transport Protein-4 in Relation to Markers of the Insulin Resistance Syndrome

• Published in: The journal of clinical endocrinology and metabolism Vol. 89; no. 1; pp. 392 - 399
• Main Authors: Gertow, K., Bellanda, M., Eriksson, P., Boquist, S., Hamsten, A., Sunnerhagen, M., Fisher, R. M.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01-01-2004; Copyright by The Endocrine Society
• Subjects: Amino Acid Sequence; Biological and medical sciences; Biological Transport; Blood Pressure; Body Mass Index; Carrier Proteins - chemistry; Carrier Proteins - genetics; Coenzyme A Ligases - metabolism; Endocrinopathies; Fasting; Fatty Acid Transport Proteins; Fatty Acids, Nonesterified - metabolism; Food; Fundamental and applied biological sciences. Psychology; Heterozygote; Homeostasis; Homozygote; Humans; Insulin - blood; Introns - genetics; Male; Medical sciences; Medicin och hälsovetenskap; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Transport Proteins; Metabolic Syndrome - genetics; Middle Aged; Models, Molecular; Molecular Sequence Data; Molecular Structure; Polymorphism, Genetic; Structure-Activity Relationship; Sweden; TECHNOLOGY; TEKNIKVETENSKAP; Triglycerides - blood; Vertebrates: endocrinology; Target tissue resistance; Pancreatic hormone; Biological marker; Lipids; Genetics; Fatty acids; Insulin; Endocrinology; Carrier protein
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2003-030682

Disturbances in fatty acid metabolism are involved in the etiology of insulin resistance and the related dyslipidemia, hypertension, and procoagulant state. The fatty acid transport proteins (FATPs) are implicated in facilitated cellular uptake of nonesterified fatty acids (NEFAs), thus potentially regulating NEFA concentrations and metabolism. The aim of this study was to investigate polymorphic loci in the FATP4 gene with respect to associations with fasting and postprandial lipid and lipoprotein variables and markers of insulin resistance in 608 healthy, middle-aged Swedish men and to evaluate possible mechanisms behind any associations observed.
Heterozygotes for a Gly209Ser polymorphism (Ser allele frequency 0.05) had significantly lower body mass index and, correcting for body mass index, significantly lower triglyceride concentrations, systolic blood pressure, insulin concentrations, and homeostasis model assessment index compared with common homozygotes. A three-dimensional model of the FATP4 protein based on structural and functional similarity with adenylate-forming enzymes revealed that the variable residue 209 is exposed in a region potentially involved in protein-protein interactions. Furthermore, the model indicated functional regions with respect to NEFA transport and acyl-coenzyme A synthase activity and membrane association.
These findings propose FATP4 as a candidate gene for the insulin resistance syndrome and provide a structural basis for understanding FATP function in NEFA transport and metabolism.