Apolipoprotein C3 Gene Variants in Nonalcoholic Fatty Liver Disease

被引:312
作者
Petersen, Kitt Falk [2 ]
Dufour, Sylvie [1 ]
Hariri, Ali [2 ]
Nelson-Williams, Carol [3 ]
Foo, Jia Nee [3 ]
Zhang, Xian-Man [2 ]
Dziura, James [2 ]
Lifton, Richard P. [1 ,2 ,3 ]
Shulman, Gerald I. [1 ,2 ,4 ]
机构
[1] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA
[2] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA
[3] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA
[4] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA
关键词
HEPATIC INSULIN-RESISTANCE; DENSITY-LIPOPROTEIN RECEPTOR; CORONARY-ARTERY-DISEASE; METABOLIC SYNDROME; STEATOSIS; POLYMORPHISMS; BINDING; CIII; HYPERTRIGLYCERIDEMIA; CHYLOMICRONS;
D O I
10.1056/NEJMoa0907295
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
BACKGROUND Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and type 2 diabetes mellitus. Whether this association has a genetic basis is unknown. METHODS In 95 healthy Asian Indian men, a group known to have a high prevalence of nonalcoholic fatty liver disease, we genotyped two single-nucleotide polymorphisms (SNPs) in the gene encoding apolipoprotein C3 (APOC3) that are known to be associated with hypertriglyceridemia (rs2854116 [T-455C] and rs2854117 [C-482T]). Plasma apolipoprotein C3 concentrations, insulin sensitivity, and hepatic triglyceride content were measured. We also measured plasma triglyceride concentrations and retinyl fatty acid ester absorption as well as plasma triglyceride clearance after oral and intravenous fat-tolerance tests. Liver triglyceride content and APOC3 genotypes were also assessed in a group of 163 healthy non-Asian Indian men. RESULTS Carriers of the APOC3 variant alleles (C-482T, T-455C, or both) had a 30% increase in the fasting plasma apolipoprotein C3 concentration, as compared with the wildtype homozygotes. They also had a 60% increase in the fasting plasma triglyceride concentration, an increase by a factor of approximately two in the plasma triglyceride and retinyl fatty acid ester concentrations after an oral fat-tolerance test, and a 46% reduction in plasma triglyceride clearance. The prevalence of nonalcoholic fatty liver disease was 38% among variant-allele carriers and 0% among wild-type homozygotes (P<0.001). The subjects with nonalcoholic fatty liver disease had marked insulin resistance. A validation study involving non-Asian Indian men confirmed the association between APOC3 variant alleles and nonalcoholic fatty liver disease. CONCLUSIONS The polymorphisms C-482T and T-455C in APOC3 are associated with nonalcoholic fatty liver disease and insulin resistance.
引用
收藏
页码:1082 / 1089
页数:8
相关论文
共 27 条
  • [1] BAECKE JAH, 1982, AM J CLIN NUTR, V36, P936
  • [2] Statins and hepatic steatosis: Perspectives from the Dallas Heart Study
    Browning, Jeffrey D.
    [J]. HEPATOLOGY, 2006, 44 (02) : 466 - 471
  • [3] Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance
    Choi, Cheol Soo
    Savage, David B.
    Kulkarni, Ameya
    Yu, Xing Xian
    Liu, Zhen-Xiang
    Morino, Katsutaro
    Kim, Sheene
    Distefano, Alberto
    Samuel, Varman T.
    Neschen, Susanne
    Zhang, Dongyan
    Wang, Amy
    Zhang, Xian-Man
    Kahn, Mario
    Cline, Gary W.
    Pandey, Sanjay K.
    Geisler, John G.
    Bhanot, Sanjay
    Monia, Brett P.
    Shulman, Gerald I.
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (31) : 22678 - 22688
  • [4] ROLE OF THE LIVER IN THE DEGRADATION OF LIPOPROTEINS
    COOPER, AD
    [J]. GASTROENTEROLOGY, 1985, 88 (01) : 192 - 205
  • [5] Polymorphisms in the fatty acid-binding protein 2 and apolipoprotein C-III genes are associated with the metabolic syndrome
    Guettier, JM
    Georgopoulos, A
    Tsai, MY
    Radha, V
    Shanthirani, S
    Deepa, R
    Gross, M
    Rao, G
    Mohan, V
    [J]. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2005, 90 (03) : 1705 - 1711
  • [6] HYPERTRIGLYCERIDEMIA AS A RESULT OF HUMAN APO-CIII GENE-EXPRESSION IN TRANSGENIC MICE
    ITO, Y
    AZROLAN, N
    OCONNELL, A
    WALSH, A
    BRESLOW, JL
    [J]. SCIENCE, 1990, 249 (4970) : 790 - 793
  • [7] Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia
    Li, WW
    Dammerman, MM
    Smith, JD
    Metzger, S
    Breslow, JL
    Leff, T
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1995, 96 (06) : 2601 - 2605
  • [8] Insulin sensitivity indices obtained from oral glucose tolerance testing - Comparison with the euglycemic insulin clamp
    Matsuda, M
    DeFronzo, RA
    [J]. DIABETES CARE, 1999, 22 (09) : 1462 - 1470
  • [9] APOC3 promoter polymorphisms C-482T and T-455C are associated with the metabolic syndrome
    Miller, Michael
    Rhyne, Jeffrey
    Chen, Hegang
    Beach, Valerie
    Ericson, Richard
    Luthra, Kalpana
    Dwivedi, Manjari
    Misra, Anoop
    [J]. ARCHIVES OF MEDICAL RESEARCH, 2007, 38 (04) : 444 - 451
  • [10] NAGATA Y, 1988, J BIOL CHEM, V263, P15151