Gene Variants Tied to NAFLD, Insulin Resistance

Two variants of the APOC3 gene, which encodes apolipoprotein C3, are associated with nonalcoholic fatty liver disease and insulin resistance, according to a new study.

Importantly, seven of the study participants who were found to carry the gene variants and who proved to have both disorders were able to reverse the steatosis and markedly improve whole-body insulin sensitivity by dieting and losing approximately 6 kg, said Dr. Kitt Falk Petersen of Yale University, New Haven, Conn., and her associates (N. Engl. J. Med. 2010;362:1082–9).

Previous studies have suggested that two single nucleotide polymorphisms, C-482T and T-455C, in the apolipoprotein C3 (APOC3) gene appeared to be associated with hypertriglyceridemia. Dr. Petersen and her colleagues recruited from the community 95 healthy men of Asian Indian background—an ethnic group known to have a high prevalence of both nonalcoholic fatty liver disease (NAFLD) and insulin resistance—for genotyping.

The men had no other risk factors such as excessive alcohol consumption, obesity, overt insulin resistance, or diabetes. Mean age was 32 years, and all the men had been of normal birth weight.

Plasma apolipoprotein C3 concentrations were 30% higher, and fasting concentrations 60% higher, in men who carried the gene variants than in those who did not. Postprandial plasma triglyceride and retinyl fatty acid ester concentrations after an oral fat-tolerance test were twice as high among carriers than among noncarriers of the single nucleotide polymorphisms (SNPs).

There were no significant differences between carriers and noncarriers in plasma concentrations of total, HDL, or LDL cholesterol, the investigators noted.

Hepatic triglyceride content, as measured by proton magnetic resonance spectroscopy, was markedly higher in men who carried the C-482T and T-455C variants than in those who did not.

Most importantly, prevalence of NAFLD was 38% in men who carried the gene variants, compared with zero prevalence among the men who did not. The men with NAFLD also had marked insulin resistance.

This link between the two SNPs and hepatic steatosis was confirmed in a second cohort of 163 non-Indian men of varied ethnic backgrounds.

A subgroup of 15 carriers of the SNP variants also showed a 46% reduction in plasma triglyceride clearance after being challenged with an intravenous lipid infusion, compared with 4 noncarriers.

“These findings support the hypothesis that the APOC3 variants we studied promote both fasting and postprandial hypertriglyceridemia by reducing triglyceride clearance,” Dr. Petersen and her colleagues said.

Taken together with other genetic studies, “these results suggest that the APOC3 variants C-482T and T-455C lead to increased plasma concentrations of apolipoprotein C3, which in turn inhibit lipoprotein lipase and triglyceride clearance, thus conferring a predisposition to both fasting and postprandial hypertriglyceridemia due to an increase in chylomicron-remnant particles.

“Increased concentrations of circulating chylomicron-remnant particles are then preferentially taken up by the liver by means of a receptor-mediated process, resulting in NAFLD and hepatic insulin resistance,” they proposed.

Modest weight reduction in seven of the subjects who followed a hypocaloric diet for 3–6 months eliminated the NAFLD and improved insulin sensitivity.

The study was supported by grants from the U.S. Public Health Service and the American Diabetes Association. Financial disclosures were reported with the text of the article at nejm.org.