Visceral obesity modulates the impact of apolipoprotein C3 gene variants on liver fat content

Objective: It has not been solved whether subjects carrying the minor alleles of the -455T > C or -482C > T single nucleotide polymorphisms (SNPs) in the apolipoprotein-C3-gene (APOC3) have an increased risk for developing fatty liver and insulin resistance. We investigated the relationships of the SNPs with hepatic APOC3 expression and hypothesized that visceral obesity may modulate the effects of these SNPs on liver fat and insulin sensitivity (IS). Methods: APOC3 mRNA expression and triglyceride content were determined in liver biopsies from 50 subjects. In a separate group (N = 330) liver fat was measured by H-1-magnetic resonance spectroscopy. IS was estimated during an oral glucose tolerance test (OGTT) and the euglycemic, hyperinsulinemic clamp (N = 222). Results: APOC3 mRNA correlated positively with triglyceride content in liver biopsies (r = 0.29, P = 0.036). Carriers of the minor alleles (-455C and -482T) tended to have higher hepatic APOC3 mRNA expression (1.80 (0.45-3.56) vs 0.77 (0.40-1.64), P = 0.09), but not higher triglyceride content (P = 0.76). In 330 subjects the genotype did not correlate with liver fat (P = 0.97) or IS (OGTT: P = 0.41; clamp: P = 0.99). However, a significant interaction of the genotype with waist circumference in determining liver fat was detected (P = 0.02) in which minor allele carriers had higher liver fat only in the lowest tertile of waist circumference (P = 0.01). In agreement, during a 9-month lifestyle intervention the minor allele carriers of the SNP -482C > T in the lowest tertile also had less decrease in liver fat (P = 0.04). Conclusions: APOC3 mRNA expression is increased in fatty liver and is regulated by SNPs in APOC3. The impact of the APOC3 SNPs on fatty liver is small and depends on visceral obesity. International Journal of Obesity (2012) 36, 774-782; doi:10.1038/ijo.2011.154; published online 9 August 2011