Abstract

Objective- In a genome-wide association scan the rs738409 C>G single nucleotide polymorphism (SNP) in the patatin-like phospholipase-3-gene (PNPLA3) was strongly associated with increased liver fat, but not with insulin resistance estimated from fasting values. We investigated whether the SNP determines liver fat independently of visceral adiposity and whether it may even play a role in protecting from insulin resistance.

Research Design and Methods- Liver fat was measured by ¹H-magnetic resonance (MR) spectroscopy and total- and visceral fat by MR tomography in 330 subjects. Insulin sensitivity (IS) was estimated during an oral glucose tolerance test (OGTT) and the euglycemic, hyperinsulinemic clamp (n=222). PNPLA3- and tumor necrosis factor (TNF)-α mRNA and triglyceride content were measured in liver biopsies from 16 subjects.

Results- Liver fat correlated strongly with IS (p<0.0001) independently of age, gender, total- and visceral fat. G allele carriers of the SNP rs738409 had higher liver fat (p<0.0001) and an odds ratio of 2.38 (95% CI, 1.37–4.20) for having fatty liver compared to C allele homozygotes. Interestingly, IS (OGTT: p=0.99; clamp: p=0.32), serum C-reactive protein levels, lipids or liver enzymes (all p>0.14) were not different among the genotypes. Additional adjustment for liver fat actually revealed increased insulin sensitivity in more obese carriers of the G allele (p=0.01). In liver biopsies triglyceride content correlated positively with expression of the pro-inflammatory gene TNF-α in C allele homozygotes (n=6, p=0.027) but not in G allele carriers (n=10, p=0.149).

Conclusions- PNPLA3 may be an important key to understand the mechanisms discriminating fatty liver with and without metabolic consequences.