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Horm Metab Res 2010; 42(12): 854-859
DOI: 10.1055/s-0030-1267186
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

A Promoter Polymorphism in the Liver-specific Fatty Acid Transport Protein 5 is Associated with Features of the Metabolic Syndrome and Steatosis

A. Auinger1 , 2 , L. Valenti3 , M. Pfeuffer1 , 2 , U. Helwig4 , J. Herrmann1 , 2 , A. L. Fracanzani3 , P. Dongiovanni3 , S. Fargion3 , J. Schrezenmeir1 , 2 , D. Rubin4
  • 1Max Rubner-Institute, Federal Research Institute of Nutrition and Food, Department of Physiology and Biochemistry of Nutrition, Kiel, Germany
  • 2Max Rubner-Institute, Federal Research Institute of Nutrition and Food, Department of Physiology and Biochemistry of Nutrition, Karlsruhe, Germany
  • 3Dipartimento di Medicina Interna, UO Medicina Interna IB, Padiglione Granelli Universita’ degli Studi di Milano, Ospedale Policlinico Mangialli e Regina Elena Fondazione IRCCS, Università di Milano, Milan, Italy
  • 4University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Clinic for General Internal Medicine, I. Medical Department, Kiel, Germany
Further Information

Publication History

received 10.03.2010

accepted 08.09.2010

Publication Date:
13 October 2010 (online)

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Abstract

The fatty acid transport protein 5 (FATP5) is exclusively expressed in the liver and is involved in hepatic lipid and bile metabolism. We investigated whether a variation in the FATP5 promoter (rs56225452) is associated with hepatic steatosis and further features of the metabolic syndrome. A total of 716 male subjects from the Metabolic Intervention Cohort Kiel (MICK) and 103 male subjects with histologically proved nonalcoholic fatty liver disease (NAFLD) were genotyped for this FATP5 polymorphism rs56225452 and phenotyped for features of the metabolic syndrome. In the MICK cohort, ALT activities, postprandial insulin, and triglyceride concentrations were higher in subjects carrying the rare A-allele compared to GG homozygotes. Accordingly, the insulin sensitivity index determined after a mixed meal and standardized glucose load was lower in A-allele carriers. NAFLD cases carrying allele A were presented with also higher ALT activities. In NAFLD subjects, the association of BMI with the degree of steatosis and glucose concentration differed across FATP5 promoter polymorphism. The FATP5 promoter polymorphism rs56225452 is associated with higher ALT activity, insulin resistance, and dyslipidemia in the general population. The impact of the BMI on the severity of steatosis in NAFLD cases seems to depend on the FATP5 polmorphism.

Key words

FATP5 - postprandial insulin resistance - hepatic steatosis - genetic variation

References

  • 1 Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study.  Hepatology. 2005;  42 44-52
    Google Scholar
  • 2 Kotronen A, Westerbacka J, Bergholm R, Pietilainen KH, Yki-Jarvinen H. Liver Fat in the Metabolic Syndrome.  J Clin Endocrinol Metab. 2007;  92 3490-3497
    Google Scholar
  • 3 Seppala-Lindroos A, Vehkavaara S, Hakkinen A-M, Goto T, Westerbacka J, Sovijarvi A, Halavaara J, Yki-Jarvinen H. Fat Accumulation in the Liver Is Associated with Defects in Insulin Suppression of Glucose Production and Serum Free Fatty Acids Independent of Obesity in Normal Men.  J Clin Endocrinol Metab. 2002;  87 3023-3028
    Google Scholar
  • 4 Gimeno RE. Fatty acid transport proteins.  Curr Opin Lipidol. 2007;  18 271-276
    Google Scholar
  • 5 Hirsch D, Stahl A, Lodish HF. A family of fatty acid transporters conserved from mycobacterium to man.  Proc Natl Acad Sci USA. 1998;  95 8625-8629
    Google Scholar
  • 6 Steinberg SJ, Mihalik SJ, Kim DG, Cuebas DA, Watkins PA. The human liver-specific homolog of very long-chain acyl-CoA synthetase is cholate: CoA ligase.  J Biol Chem. 2000;  275 15605-15608
    Google Scholar
  • 7 Hubbard B, Doege H, Punreddy S, Wu H, Huang X, Kaushik VK, Mozell RL, Byrnes JJ, Stricker-Krongrad A, Chou CJ, Tartaglia LA, Lodish HF, Stahl A, Gimeno RE. Mice deleted for fatty acid transport protein 5 have defective bile acid conjugation and are protected from obesity.  Gastroenterology. 2006;  130 1259-1269
    Google Scholar
  • 8 Doege H, Grimm D, Falcon A, Tsang B, Storm TA, Xu H, Ortegon AM, Kazantzis M, Kay MA, Stahl A. Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia.  J Biol Chem. 2008;  283 22186-22192
    Google Scholar
  • 9 Doege H, Baillie RA, Ortegon AM, Tsang B, Wu Q, Punreddy S, Hirsch D, Watson N, Gimeno RE, Stahl A. Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis.  Gastroenterology. 2006;  130 1245-1258
    Google Scholar
  • 10 Fisher E, Nitz I, Lindner I, Rubin D, Boeing H, Mohlig M, Hampe J, Schreiber S, Schrezenmeir J, Doring F. Candidate gene association study of type 2 diabetes in a nested case-control study of the EPIC-Potsdam cohort – role of fat assimilation.Mol nutr Food Res 2007;51:185–191. 
    Google Scholar
  • 11 Rubin D, Helwig U, Nothnagel M, Folsch U, Schreiber S, Schrezenmeir J. Association of postprandial and fasting triglycerides with traits of the metabolic syndrome in the Metabolic Intervention Cohort Kiel (MICK).  Eur J Endocrinol. 2010;  162 719-727
    Google Scholar
  • 12 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
    Google Scholar
  • 13 Mari A, Pacini G, Murphy E, Ludvik B, Nolan JJ. A Model-Based Method for Assessing Insulin Sensitivity From the Oral Glucose Tolerance Test.  Diabetes Care. 2001;  24 539-548
    Google Scholar
  • 14 Fargion S, Mattioli M, Fracanzani AL, Sampietro M, Tavazzi D, Fociani P, Taioli E, Valenti L, Fiorelli G. Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis.  Am J Gastroenterol. 2001;  96 2448-2455
    Google Scholar
  • 15 Caballeria L, Pera G, Auladell MA, Toran P, Munoz L, Miranda D, Aluma A, Casas JD, Sanchez C, Gil D, Auba J, Tibau A, Canut S, Bernad J, Aizpurua MM. Prevalence and factors associated with the presence of nonalcoholic fatty liver disease in an adult population in Spain.  Eur J Gastroenterol Hepatol. 2010;  22 24-32
    Google Scholar
  • 16 Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A. Design and validation of a histological scoring system for nonalcoholic fatty liver disease.  Hepatology. 2005;  41 1313-1321
    Google Scholar
  • 17 Hampe J, Shaw SH, Saiz R, Leysens N, Lantermann A, Mascheretti S, Lynch NJ, MacPherson AJ, Bridger S, van Deventer S, Stokkers P, Morin P, Mirza MM, Forbes A, Lennard-Jones JE, Mathew CG, Curran ME, Schreiber S. Linkage of inflammatory bowel disease to human chromosome 6p.  Am J Hum Genet. 1999;  65 1647-1655
    Google Scholar
  • 18 Wingender E, Dietze P, Karas H, Knuppel R. TRANSFAC: a database on transcription factors and their DNA binding sites.  Nucl Acids Res. 1996;  24 238-241
    Google Scholar
  • 19 Merika M, Orkin SH. DNA-binding specificity of GATA family transcription factors.  Mol Cell Biol. 1993;  13 3999-4010
    Google Scholar
  • 20 Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps.  Bioinformatics. 2005;  21 263-265
    Google Scholar
  • 21 Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K. dbSNP: the NCBI database of genetic variation.  Nucl Acids Res. 2001;  29 308-311
    Google Scholar
  • 22 Goto T, Onuma T, Takebe K, Kral JG. The influence of fatty liver on insulin clearance and insulin resistance in non-diabetic Japanese subjects.  Int J Obes Relat Metab Disord. 1995;  19 841-845
    Google Scholar
  • 23 Sasaki S, Masaki N, Yashiro H, Kudo M, Kimura K, Takebe K. Degradation of insulin in perfused liver and skeletal muscle and insulin secretion in perfused pancreas of liver injury rat.  Horm Metab Res. 1981;  13 561-564
    Google Scholar
  • 24 Hwang JH, Stein DT, Barzilai N, Cui MH, Tonelli J, Kishore P, Hawkins M. Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies.  Am J Physiol Endocrinol Metab. 2007;  293 E1663-E1669
    Google Scholar
  • 25 Schwarz J-M, Linfoot P, Dare D, Aghajanian K. Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets.  Am J Clin Nutr. 2003;  77 43-50
    Google Scholar
  • 26 Adiels M, Taskinen MR, Packard C, Caslake MJ, Soro-Paavonen A, Westerbacka J, Vehkavaara S, Häkkinen A, Olofsson SO, Yki-Järvinen H. Overproduction of large VLDL particles is driven by increased liver fat content in man.  Diabetologia. 2006;  49 755-765
    Google Scholar
  • 27 Pedrini MT, Kranebitter M, Niederwanger A, Kaser S, Engl J, Debbage P, Huber LA, Patsch JR. Human triglyceride-rich lipoproteins impair glucose metabolism and insulin signalling in L6 skeletal muscle cells independently of non-esterified fatty acid levels.  Diabetologia. 2005;  48 756-766
    Google Scholar
  • 28 Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.  J Clin Invest. 2005;  115 1343-1351
    Google Scholar
  • 29 Rijkelijkhuizen JM, Doesburg T, Girman CJ, Mari A, Rhodes T, Gastaldelli A, Nijpels G, Dekker JM. Hepatic fat is not associated with beta-cell function or postprandial free fatty acid response.  Metabolism. 2009;  58 196-203
    Google Scholar
  • 30 Westerbacka J, Corner A, Tiikkainen M, Tamminen M, Vehkavaara S, Häkkinen AM, Fredriksson J, Yki-Järvinen H. Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: implications for sex differences in markers of cardiovascular risk.  Diabetologia. 2004;  47 1360-1369
    Google Scholar

Correspondence

A. Auinger

Max Rubner-Institut

Federal Research Institute of

Nutrition and Food

Department of Physiology and

Biochemistry of Nutrition

Hermann-Weigmann-Straße 1

24103 Kiel

Germany

Phone: +49/431/609 2506

Fax: +49/431/609 2472

Email: Annegret.Auinger@mri.bund.de

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