• Kitt Falk Petersen, Sylvie Dufour, Ali Hariri, Carol Nelson-Williams, Jia Nee Foo, Xian-Man Zhang, James Dziura, Richard P Lifton, and Gerald I Shulman.
• Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
• N. Engl. J. Med. 2010 Mar 25; 362 (12): 108210891082-9.

BackgroundNonalcoholic fatty liver disease is associated with hepatic insulin resistance and type 2 diabetes mellitus. Whether this association has a genetic basis is unknown.MethodsIn 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.ResultsCarriers 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 wild-type 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.ConclusionsThe polymorphisms C-482T and T-455C in APOC3 are associated with nonalcoholic fatty liver disease and insulin resistance.2010 Massachusetts Medical Society

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