Lack of effect of apolipoprotein C3 polymorphisms on indices of liver steatosis, lipid profile and insulin resistance in obese Southern Europeans

Lipids in Health and Disease

Marco G Baroni³  Frida Leonetti¹  Efisio Cossu³  Federica Coccia¹  Francesca Scano³  Maria A Burza²  Michela Incani³  Cristina Maglio²  Stefano Romeo²  Federica Sentinelli³ 

[1] Department of Clinical Sciences, University of Rome La Sapienza, Rome, Italy;University of Gothenburg, Department of Molecular and Clinical Medicine, Sahlgrenska Center for Cardiovascolar and Metabolic Research, Sweden;Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Italy

关键词: atherogenic dyslipidemia;    HDL;    tryglicerides;    obesity;    BMI;    NAFLD;    hepatic transaminases;   

Others  :  1212627
DOI  :  10.1186/1476-511X-10-93

 received in 2011-05-02, accepted in 2011-06-10,  发布年份 2011

【 摘 要 】

Background

Apolipoprotein C3 (APOC3) is a component of triglyceride-rich lipoproteins, and APOC3 rs2854116 and rs2854117 polymorphisms have been associated with non-alcoholic fatty liver disease, hypertriglyceridaemia, and insulin-resistance.

Objective

To determine if the APOC3 variants alter the susceptibility of obese subjects to develop liver damage, hypertrigliceridaemia, and insulin-resistance.

Methods

The study was carried out on 585 unrelated obese Italians (median body mass index BMI = 41 kg/m²) who were genotyped for the rs2854116 and rs2854117 variants. All participants underwent oral glucose tolerance tests (OGTT), with measurement of glucose, insulin, lipid parameters. Indices of insulin-resistance (HOMA and ISI) were calculated. Alanine transaminase (ALT) and aspartate transaminase (AST) were used as markers of liver injury.

Results

The study subjects were divided into two groups: those homozygous for the wild-type alleles at both SNPs (-482C and -455T alleles) and those who were carriers of at least one variant allele or both (-482T, -455C or both). Also each SNP was analysed independently. No significant differences were found in ALT and AST levels and in the lipid profile between the two groups. Insulin concentrations, glucose tolerance and insulin sensitivity were similar in the two groups.

Conclusion

We did not identify any significant association between APOC3 polymorphisms and fatty liver disease, lipids, and insulin-resistance in obese subjects, thus not confirming the suggested role of these APOC3 gene sequence variants.

【 授权许可】

   
2011 Sentinelli et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Roden M: Mechanisms of disease: hepatic steatosis in type 2 diabetes-pathogenesis and clinical relevance. Nat Clin Pract Endocrinol Metab 2006, 2:335-348.
• [2]Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P: The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005, 129:113-121.
• [3]Westerbacka J, Cornér 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.
• [4]Schindhelm RK, Diamant M, Dekker JM, Tushuizen ME, Teerlink T, Heine RJ: Alanine aminotransferase as a marker of non-alcoholic fatty liver disease in relation to type 2 diabetes mellitus and cardiovascular disease. Diabetes Metab Res Rev 2006, 22(6):437-443.
• [5]Petersen KF, Dufour S, Hariri A, Nelson-Williams C, Foo JN, Zhang XM, Dziura J, Lifton RP, Shulman GI: Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 2010, 362:1082-1089.
• [6]Jong MC, Hofker MH, Havekes LM: Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3. Arterioscler Thromb Vasc Biol 1999, 19:472-4847.
• [7]Fredenrich A, Giroux LM, Tremblay M, Krimbou L, Davignon J, Cohn JS: Plasma lipoprotein distribution of apoC-III in normolipidemic and hypertriglyceridemic subjects: comparison of the apoC-III to apoE ratio in different lipoprotein fractions. J Lipid Res 1997, 38:1421-1432.
• [8]Ginsberg HN, Le NA, Goldberg IJ, Gibson JC, Rubinstein A, Wang-Iverson P, Norum R, Brown WV: Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J Clin Invest 1986, 78:1287-1295.
• [9]McConathy WJ, Gesquiere JC, Bass H, Tartar A, Fruchart JC, Wang CS: Inhibition of lipoprotein lipase activity by synthetic peptides of apolipoprotein C-III. J Lipid Res 1992, 33:995-1003.
• [10]Kozlitina J, Boerwinkle E, Cohen JC, Hobbs HH: Dissociation between APOC3 variants, hepatic triglyceride content and insulin resistance. Hepatology 2011, 53(2):467-474.
• [11]Romeo S, Sentinelli F, Dash S, Yeo GS, Savage DB, Leonetti F, Capoccia D, Incani M, Maglio C, Iacovino M, O'Rahilly S, Baroni MG: Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent. Int J Obes 2010, 34:190-194.
• [12]Romeo S, Sentinelli F, Cambuli VM, Incani M, Congiu T, Matta V, Pilia S, Huang-Doran I, Cossu E, Loche S, Baroni MG: The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life. J Hepatol 2010, 53(2):335-338.
• [13]Wejstål R, Hansson G, Lindholm A, Norkrans G: Persistent alanine aminotransferase elevation in healthy Swedish blood donors-mainly caused by obesity. Vox Sang 1988, 55:152-156.
• [14]Romeo S, Sentinelli F, Cavallo MG, Leonetti F, Fallarino M, Mariotti S, Baroni MG: Search for genetic variants of the SYNTAXIN 1A (STX1A) gene: the -352 A > T variant in the STX1A promoter associates with impaired glucose metabolism in an Italian obese population. Int J Obes 2008, 32:413-420.
• [15]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.
• [16]Matsuda M, DeFronzo RA: Insulin sensitivity indices obtained from oral glucose tolerance testing:comparison with the euglycemic insulin clamp. Diabetes Care 1999, 22:1462-1470.
• [17]Hill WG, Robertson A: Linkage disequilibrium of finite populations. Theor Appl Genet 1968, 38:226-231.
• [18]Lewontin RC: The interaction of selection and linkage 1. General considerations: heterotic models. Genetics 1984, 49:49-67.
• [19]Li WW, Dammerman MM, Smith JD, Metzger S, Breslow JL, Leff T: Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia. J Clin Invest 1995, 96:2601-2605.
• [20]Cauchi S, Nead KT, Choquet H, Horber F, Potoczna N, Balkau B, Marre M, Charpentier G, Froguel P, Meyre D: The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies. BMC Med Genet 2008, 22:45-49.
• [21]Ludovico O, Pellegrini F, Di Paola R, Minenna A, Mastroianno S, Cardellini M, Marini MA, Andreozzi F, Vaccaro O, Sesti G, Trischitta V: Heterogeneous effect of peroxisome proliferator-activated receptor gamma2 Ala12 variant on type 2 diabetes risk. Obesity 2007, 15:1076-1081.
• [22]Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, Vianello L, Zanuso F, Mozzi F, Milani S, Conte D, Colombo M, Sirchia G: Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002, 137:1-10.
• [23]Pratt DS, Kaplan MM: Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med 2000, 342:1266-1271.
• [24]Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M: Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003, 37:917-923.
• [25]Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, Khalil L, Turpin G, Opolon P, Poynard T: Liver fibrosis in overweight patients. Gastroenterology 2000, 118:1117-1123.
• [26]Richart C, Auguet T, Terra X: Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 2010, 363:193-194.
• [27]Chen M, Breslow JL, Li W, Leff T: Transcriptional regulation of the apo C-III gene by insulin in diabetic mice: correlation with changes in plasma triglyceride levels. J Lipid Res 1994, 35:1918-1924.
• [28]Angelico F, Del Ben M, Conti R, Francioso S, Feole K, Fiorello S, Cavallo MG, Zalunardo B, Lirussi F, Alessandri C, Violi F: Insulin resistance, the metabolic syndrome, and non-alcoholic fatty liver disease. J Clin Endocrinol Metab 2005, 90:1578-1582.
• [29]Amarapurka DN, Amarapurkar AD, Patel ND, Agal S, Baigal R, Gupte P, Pramanik S: Nonalcoholic steatohepatitis (NASH) with diabetes: predictors of liver fibrosis. Ann Hepatol 2006, 5:30-33.