Abstract 324: The Apolipoprotein A-IV T347S Polymorphism is Associated with Severe Hepatic Steatosis in Obese Subjects Undergoing Bariatric Surgery

Abstract

Background: We recently reported that hepatic apolipoprotein A-IV (apoA-IV) gene expression is increased in mouse models of steatosis and is positively correlated with liver triglyceride (TG) content. The most common human apoA-IV polymorphism T347S (rs675) decreases its lipid affinity and is associated with increased adiposity in population studies. Hypothesis: 347S allele carriers will exhibit increased hepatic TG content in conditions predisposing to hepatic steatosis. Methods: We examined the impact of the 347S allele on liver TG content in a cohort of very obese humans. Total hepatic mRNA was extracted from snap frozen tissue obtained from 40 obese subjects (11 male, 29 female) at the time of bariatric surgery. ApoA-IV abundance was quantitated by RT-PCR; copy numbers were normalized to GAPDH. Presence of the T347S polymorphism and the next most common apoA-IV allele, S127N (rs5104), was determined by cDNA sequencing. Liver total TG was measured in solvent extracts by GLC and normalized as mg TG/g protein. Results: Mean BMI in the cohort was 43.8 ± 1.5 kg/m 2 ; T347S allele frequency was 0.38 and S127N allele frequency was 0.23; 16/40 (40%) had severe steatosis (hepatic TG content > 400 mg TG/g protein). There was no difference in total hepatic apoA-IV mRNA abundance among carriers of the wild type and variant alleles; mean liver TG content was highest in subjects carrying a 347S allele; a significantly higher percentage of subjects carrying a 347S allele, but not a 127N allele, had severe steatosis (P=0.024). Conclusions: These data establish that the apoA-IV 347S allele is associated with severe hepatic steatosis in a cohort of obese subjects, and suggest that apoA-IV genotype plays a role in hepatic lipid metabolism. As apoA-IV facilitates hepatic TG export by enabling secretion of larger VLDL particles, the impact of the 347S allele on hepatic TG content in the absence of altered gene expression suggests that its reduced lipid affinity may impair VLDL particle expansion.