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

Department of Medicine (K.G., P.E., S.B., A.H., R.M.F.), Atherosclerosis Research Unit, King Gustaf V Research Institute, and Department of Medical Biochemistry and Biophysics (M.S.), Karolinska Institutet, S-171 76 Stockholm, Sweden; and Department of Organic Chemistry (M.B.), University of Padova, 35131 Padova, Italy

Address all correspondence and requests for reprints to: Rachel Fisher, King Gustaf V Research Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail: rachel.fisher{at}medks.ki.se.

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.

This work was supported by grants from the Swedish Medical Research Council (project 8691), the Söderberg Foundation, the Swedish Heart and Lung Foundation, the Swedish Institute, the Swedish National Network and Graduate School for Cardiovascular Research, the Professor Nanna Svartz Foundation, the Åke Wiberg Foundation, the Nilsson-Ehle Foundation, the Fredrik and Ingrid Thuring Foundation, the Gamla Tjänarinnor Foundation, and the Sigurd and Elsa Goljes Foundation.

Present address for M.S.: Molecular Biotechnology, IFM, Linköping University, S-581 83 Linköping, Sweden.

Abbreviations: acyl-CoA, Acyl-coenzyme A; apo, apolipoprotein; BMI, body mass index; FA, fatty acid; FACS, fatty acyl-CoA synthase; FATP, fatty acid transport protein; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; LDL, low-density lipoprotein; NEFA, nonesterified fatty acid; OFTT, oral fat tolerance test; SBP, systolic blood pressure; seACS, Salmonella enterica acetyl-CoA synthase; S_f, Svedberg floatation rate; SNP, single-nucleotide polymorphism; TG, triglyceride; VLDL, very low-density lipoprotein.

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