PNPLA3 variant I148M is associated with altered hepatic lipid composition in humans

Aims/hypothesis The common sequence variant I148M of the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3) is associated with increased hepatic triacylglycerol (TAG) content, but not with insulin resistance, in humans. The PNPLA3(I148M) variant was previously reported to alter the specificity of the encoded enzyme and subsequently affect lipid composition. Methods We analysed the fatty acid composition of five lipid fractions from liver tissue samples from 52 individuals, including 19 carriers of the minor PNPLA3(I148M) variant. Results PNPLA3(I148M) was associated with a strong increase (1.75-fold) in liver TAGs, but with no change in other lipid fractions. PNPLA3(I148M) minor allele carriers had an increased n-3 polyunsaturated fatty acid (PUFA) alpha-linolenic acid content and reductions in several n-6 PUFAs in the liver TAG fraction. Furthermore, there was a strong inverse correlation between n-6 PUFA and TAG content independent of PNPLA3 genotype. In a multivariate model including liver fat content, PNPLA3 genotype and fatty acid composition, two significant differences could be exclusively attributed to the PNPLA3(I148M) minor allele: reduced stearic acid and increased alpha-linolenic acid content in the hepatic TAG fraction. Conclusions These changes therefore suggest a mechanism to explain the PNPLA3(I148M)-dependent increase in liver fat content without causing insulin resistance. Stearic acid can induce insulin resistance, whereas alpha-linolenic acid may protect against it.