A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents

Abstract

The genetic factors associated with susceptibility to nonalcoholic fatty liver disease (NAFLD) in pediatric obesity remain largely unknown. Recently, a nonsynonymous single-nucleotide polymorphism (rs738409), in the patatin-like phospholipase 3 gene (PNPLA3) has been associated with hepatic steatosis in adults. In a multiethnic group of 85 obese youths, we genotyped the PNLPA3 single-nucleotide polymorphism, measured hepatic fat content by magnetic resonance imaging and insulin sensitivity by the insulin clamp. Because PNPLA3 might affect adipogenesis/lipogenesis, we explored the putative association with the distribution of adipose cell size and the expression of some adipogenic/lipogenic genes in a subset of subjects who underwent a subcutaneous fat biopsy. Steatosis was present in 41% of Caucasians, 23% of African Americans, and 66% of Hispanics. The frequency of PNPLA3(rs738409) G allele was 0.324 in Caucasians, 0.183 in African Americans, and 0.483 in Hispanics. The prevalence of the G allele was higher in subjects showing hepatic steatosis. Surprisingly, subjects carrying the G allele showed comparable hepatic glucose production rates, peripheral glucose disposal rate, and glycerol turnover as the CC homozygotes. Carriers of the G allele showed smaller adipocytes than those with CC genotype (P = 0.005). Although the expression of PNPLA3, PNPLA2, PPARγ2(peroxisome proliferator-activated receptor gamma 2), SREBP1c(sterol regulatory element binding protein 1c), and ACACA(acetyl coenzyme A carboxylase) was not different between genotypes, carriers of the G allele showed lower leptin (LEP)(P = 0.03) and sirtuin 1 (SIRT1) expression (P = 0.04). Conclusion A common variant of the PNPLA3 gene confers susceptibility to hepatic steatosis in obese youths without increasing the level of hepatic and peripheral insulin resistance. The rs738409 PNPLA3 G allele is associated with morphological changes in adipocyte cell size.

The Role of Inflammatory Mediators in the Pathogenesis of Nonalcoholic Fatty Liver Disease

“…These authors also reported that this allele was most common in Hispanics who are known as ethnic group with the highest prevalence of NAFLD [10]. According to another study in a multiethnic group of obese children and adolescents, the presence of this G allele variant increased an susceptibility to the hepatic steatosis and it also caused morphologic changes in the size of adipocytes without increasing hepatic or peripheral insulin resistance [11]. In the second hit process, oxidative stress is thought to play a crucial role.…”

Characterization of genome-wide transcriptional changes in liver and adipose tissues of ZDF (fa/fa) rats fed R-α-lipoic acid by next-generation sequencing

“…NAFLD with a nonsynonymous single nucleotide polymorphism in Pnpla3 (14,34,37), which enhances hepatic lipid synthesis because of a gain of function (39). Yet deletion of Pnpla3 in mice does not cause hepatosteatosis or metabolic syndrome (3,9).…”

Genetic determinants of hepatic steatosis in man

“…This was supported by data from Kantartzis et al, who also found no association between I148M and insulin sensitivity as measured by the oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp in 222 subjects ( 152 ). More recently, Santoro et al demonstrated that obese children and adolescents carrying I148M had comparable hepatic glucose production, peripheral glucose disposal, and glycerol turnover to those homozygous for the wild-type allele ( 153 ). Interestingly, they also showed that adipocytes from a subcutaneous fat biopsy were Overall, the two SNPs in PNPLA3 , I148M and S453I, accounted for an astonishing 72% of the ethnic differences in hepatic fat content ( 144 ).…”