MTTP-297H polymorphism reduced serum cholesterol but increased risk of non-alcoholic fatty liver disease-a cross-sectional study

BMC Medical Genetics

Kung-Kai Kuo³  Yi-Hsin Connie Yang¹  Pi-Chen Lin⁵  He-Jiun Jiang⁵  Yeng-Tseng Wang²  Mei-Yueh Lee⁵  Pi-Jung Hsiao⁴ 

[1]School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan

[2]Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

[3]Division of Hepatobiliopancreatic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

[4]School of Medicine, College of Medicine, Kaohsiung Medical University, 100 Tzyou 1st Rd, Kaohsiung 807, Taiwan

[5]Division of Endocrinology and Metabolism, Department of Internal Medicine

[6] Kaohsiung Municipal Siaogang Hospital, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

关键词: Q297H polymorphism;    Non-alcoholic fatty liver disease (NAFLD);    Non-HDL-C;    LDL-C;    Apob-containing lipoproteins;    Microsomal triglyceride transfer protein (MTP);   

Others  :  1230639
DOI  :  10.1186/s12881-015-0242-6

 received in 2015-04-21, accepted in 2015-10-05,  发布年份 2015

【 摘 要 】

Background

Microsomal triglyceride transfer protein (MTP) works to lipidate and assemble the apoB-containing lipoproteins in liver. It closely links up the hepatic secretion of lipid to regulate serum lipid and atherosclerosis. Cases of MTTP gene mutation is characterized by abetalipoproteinemia and remarkable hepatic steatosis or cirrhosis. Several MTTP polymorphisms have been reported relating to metabolic syndrome, hyperlipidemia and steatohepatitis. We supposed the regulation of serum lipids and risk of non-alcoholic fatty liver disease (NAFLD) formation may be modified by individual susceptibility related to the MTTP polymorphisms.

Methods and results

A cross-sectional population of 1193 subjects, 1087 males and 106 females mean aged 45.9 ± 8.9 years, were enrolled without recognized secondary hyperlipidemia. Fasting serum lipid, insulin, and non-esterified fatty acid were assessed and transformed to insulin resistance index, HOMA-IR and Adipo-IR. After ruling out alcohol abuser, non-alcoholic fatty liver disease (NAFLD) was diagnosed by abdominal ultrasound. Five common MTTP polymorphisms (promoter -493G/T, E98D, I128T, N166S, and Q297H) were conducted by TaqMan assay. Multivariate regression analysis was used to estimate their impact on serum lipid and NAFLD risk. Assessment revealed a differential impact on LDL-C and non-HDL-C, which were sequentially determined by the Q297H polymorphism, insulin resistance, body mass index and age. Carriers of homozygous minor allele (297H) had significantly lower LDL-C and non-HDL-C but higher risk for NAFLD. Molecular modeling of the 297H variant demonstrated higher free energy, potentially referring to an unstable structure and functional sequence.

Conclusion

These results evidenced the MTTP polymorphisms could modulate the lipid homeostasis to determine the serum lipids and risk of NAFLD. The MTTP 297H polymorphism interacted with age, insulin resistance and BMI to decrease serum apoB containing lipoproteins (LDL-C and non-HDL-C) but increase the risk of NAFLD formation.

【 授权许可】

   
2015 Hsiao et al.

【 图 表 】

Fig. 1.

Fig. 2.

【 参考文献 】

• [1]Miller SA, Burnett JR, Leonis MA, McKnight CJ, van Bockxmeer FM, Hooper AJ. Novel missense MTTP gene mutations causing abetalipoproteinemia. Biochim Biophys Acta. 2014; 1842(10):1548-54.
• [2]Hussain MM, Rava P, Walsh M, Rana M, Iqbal J. Multiple functions of microsomal triglyceride transfer protein. Nutr Metabol. 2012; 9:14. BioMed Central Full Text
• [3]Zamel R, Khan R, Pollex RL, Hegele RA. Abetalipoproteinemia: two case reports and literature review. Orphanet J Rare Dis. 2008; 3:19. BioMed Central Full Text
• [4]Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia. Curr Opin Lipidol. 2014; 25(3):161-8.
• [5]Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia. 2012; 55(4):885-904.
• [6]Koo SH. Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis. Clin Mol Hepatol. 2013; 19(3):210-5.
• [7]Kawano Y, Cohen DE. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J Gastroenterol. 2013; 48(4):434-41.
• [8]Hussain MM, Shi J, Dreizen P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res. 2003; 44(1):22-32.
• [9]Di Filippo M, Moulin P, Roy P, Samson-Bouma ME, Collardeau-Frachon S, Chebel-Dumont S et al.. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J Hepatol. 2014; 61(4):891-902.
• [10]Khatun I, Walsh MT, Hussain MM. Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia. J Lipid Res. 2013; 54(6):1541-9.
• [11]Zak A, Jachymova M, Tvrzicka E, Vecka M, Duffkova L, Zeman M et al.. The influence of polymorphism of -493G/T MTP gene promoter and metabolic syndrome on lipids, fatty acids and oxidative stress. J Nutr Biochem. 2008; 19(9):634-41.
• [12]Peng XE, Wu YL, Lu QQ, Hu ZJ, Lin X. MTTP polymorphisms and susceptibility to non-alcoholic fatty liver disease in a Han Chinese population. Liver Int. 2014; 34(1):118-28.
• [13]Musso G, Gambino R, Cassader M. Lipoprotein metabolism mediates the association of MTP polymorphism with beta-cell dysfunction in healthy subjects and in nondiabetic normolipidemic patients with nonalcoholic steatohepatitis. J Nutr Biochem. 2010; 21(9):834-40.
• [14]Chen SP, Tan KC, Lam KS. Effect of the microsomal triglyceride transfer protein -493 G/T polymorphism and type 2 diabetes mellitus on LDL subfractions. Atherosclerosis. 2003; 167(2):287-92.
• [15]Aminoff A, Ledmyr H, Thulin P, Lundell K, Nunez L, Strandhagen E et al.. Allele-specific regulation of MTTP expression influences the risk of ischemic heart disease. J Lipid Res. 2010; 51(1):103-11.
• [16]Lin MC, Gordon D, Wetterau JR. Microsomal triglyceride transfer protein (MTP) regulation in HepG2 cells: insulin negatively regulates MTP gene expression. J Lipid Res. 1995; 36(5):1073-81.
• [17]Roy A, Xu D, Poisson J, Zhang Y. A protocol for computer-based protein structure and function prediction. J Vis Exp. 2011; 57: Article ID e3259
• [18]Worth CL, Preissner R, Blundell TL. SDM–a server for predicting effects of mutations on protein stability and malfunction. Nucleic Acids Res. 2011; 39(Web Server issue):W215-22.
• [19]Karpe F, Lundahl B, Ehrenborg E, Eriksson P, Hamsten A. A common functional polymorphism in the promoter region of the microsomal triglyceride transfer protein gene influences plasma LDL levels. Arterioscler Thromb Vasc Biol. 1998; 18(5):756-61.
• [20]Lundahl B, Skoglund-Andersson C, Caslake M, Bedford D, Stewart P, Hamsten A et al.. Microsomal triglyceride transfer protein -493T variant reduces IDL plus LDL apoB production and the plasma concentration of large LDL particles. Am J Physiol Endocrinol Metab. 2006; 290(4):E739-45.
• [21]St-Pierre J, Lemieux I, Miller-Felix I, Prud’homme D, Bergeron J, Gaudet D et al.. Visceral obesity and hyperinsulinemia modulate the impact of the microsomal triglyceride transfer protein -493G/T polymorphism on plasma lipoprotein levels in men. Atherosclerosis. 2002; 160(2):317-24.
• [22]Bohme M, Grallert H, Fischer A, Gieger C, Nitz I, Heid I et al.. MTTP variants and body mass index, waist circumference and serum cholesterol level: Association analyses in 7582 participants of the KORA study cohort. Mol Genet Metab. 2008; 95(4):229-32.
• [23]Talmud PJ, Palmen J, Miller G, Humphries SE. Effect of microsomal triglyceride transfer protein gene variants (-493G>T, Q95H and H297Q) on plasma lipid levels in healthy middle-aged UK men. Ann Hum Genet. 2000; 64(Pt 4):269-76.
• [24]Ledmyr H, Karpe F, Lundahl B, McKinnon M, Skoglund-Andersson C, Ehrenborg E. Variants of the microsomal triglyceride transfer protein gene are associated with plasma cholesterol levels and body mass index. J Lipid Res. 2002; 43(1):51-8.
• [25]Zheng W, Wang L, Su X, Hu XF. MTP -493G>T polymorphism and susceptibility to nonalcoholic fatty liver disease: a meta-analysis. DNA Cell Biol. 2014; 33(6):361-9.
• [26]Gordon DA, Jamil H, Gregg RE, Olofsson SO, Boren J. Inhibition of the microsomal triglyceride transfer protein blocks the first step of apolipoprotein B lipoprotein assembly but not the addition of bulk core lipids in the second step. J Biol Chem. 1996; 271(51):33047-53.
• [27]Lehner R, Lian J, Quiroga AD. Lumenal lipid metabolism: implications for lipoprotein assembly. Arterioscler Thromb Vasc Biol. 2012; 32(5):1087-93.
• [28]Ledmyr H, Ottosson L, Sunnerhagen M, Ehrenborg E. The Ile128Thr polymorphism influences stability and ligand binding properties of the microsomal triglyceride transfer protein. J Lipid Res. 2006; 47(7):1378-85.
• [29]Segrest JP, Jones MK, Dashti N. N-terminal domain of apolipoprotein B has structural homology to lipovitellin and microsomal triglyceride transfer protein: a “lipid pocket” model for self-assembly of apob-containing lipoprotein particles. J Lipid Res. 1999; 40(8):1401-16.
• [30]Dashti N, Gandhi M, Liu X, Lin X, Segrest JP. The N-terminal 1000 residues of apolipoprotein B associate with microsomal triglyceride transfer protein to create a lipid transfer pocket required for lipoprotein assembly. Biochemistry. 2002; 41(22):6978-87.
• [31]Raabe M, Veniant MM, Sullivan MA, Zlot CH, Bjorkegren J, Nielsen LB et al.. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice. J Clin Invest. 1999; 103(9):1287-98.
• [32]Khatun I, Zeissig S, Iqbal J, Wang M, Curiel D, Shelness GS et al.. Phospholipid transfer activity of microsomal triglyceride transfer protein produces apolipoprotein B and reduces hepatosteatosis while maintaining low plasma lipids in mice. Hepatology. 2012; 55(5):1356-68.
• [33]Dikkers A, Annema W, de Boer JF, Iqbal J, Hussain MM, Tietge UJ. Differential impact of hepatic deficiency and total body inhibition of MTP on cholesterol metabolism and RCT in mice. J Lipid Res. 2014; 55(5):816-25.
• [34]Sahebkar A, Watts GF. New LDL-cholesterol lowering therapies: pharmacology, clinical trials, and relevance to acute coronary syndromes. Clin Ther. 2013; 35(8):1082-98.
• [35]Rader DJ, Kastelein JJ. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation. 2014; 129(9):1022-32.
• [36]Thomas GS, Cromwell WC, Ali S, Chin W, Flaim JD, Davidson M. Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2013; 62(23):2178-84.
• [37]Davis KA, Miyares MA. Lomitapide: a novel agent for the treatment of homozygous familial hypercholesterolemia. Am J Health Syst Pharm. 2014; 71(12):1001-8.
• [38]Lin M, Zhao S, Shen L, Xu D. Potential approaches to ameliorate hepatic fat accumulation seen with MTP inhibition. Drug Saf. 2014; 37(4):213-24.
• [39]Hsiao PJ, Kuo KK, Shin SJ, Yang YH, Lin WY, Yang JF et al.. Significant correlations between severe fatty liver and risk factors for metabolic syndrome. J Gastroenterol Hepatol. 2007; 22(12):2118-23.