Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.
Hepatology. 2010 Oct;52(4):1281-90. doi: 10.1002/hep.23832.
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).
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.
非酒精性脂肪性肝病（NAFLD）易感性相关的遗传因素在儿科肥胖中仍然很大程度上未知。最近，patatin 样磷脂酶 3 基因（PNPLA3）中的一个非同义单核苷酸多态性（rs738409）与成人肝脂肪变性有关。在一个多民族的 85 名肥胖青少年组中，我们对 PNPLA3 单核苷酸多态性进行了基因分型，通过磁共振成像测量肝脂肪含量，并通过胰岛素钳夹测量胰岛素敏感性。因为 PNPLA3 可能影响脂肪生成/脂肪生成，所以我们在接受皮下脂肪活检的亚组中探索了与脂肪细胞大小分布和一些脂肪生成/脂肪生成基因表达的潜在关联。在白人中，41%存在脂肪变性，在非裔美国人中为 23%，在西班牙裔中为 66%。PNPLA3(rs738409)G 等位基因的频率在白种人中为 0.324，在非裔美国人中为 0.183，在西班牙裔中为 0.483。在存在肝脂肪变性的患者中，G 等位基因的频率更高。令人惊讶的是，携带 G 等位基因的患者与 CC 纯合子相比，肝葡萄糖生成率、外周葡萄糖处置率和甘油周转率相当。与 CC 基因型相比，G 等位基因携带者的脂肪细胞较小（P=0.005）。尽管基因型之间 PNPLA3、PNPLA2、PPARγ2（过氧化物酶体增殖物激活受体γ 2）、SREBP1c（固醇调节元件结合蛋白 1c）和 ACACA（乙酰辅酶 A 羧化酶）的表达没有差异，但 G 等位基因携带者的瘦素（LEP）表达较低（P=0.03）和 SIRT1 表达较低（P=0.04）。
PNPLA3 基因的常见变异赋予肥胖青少年发生肝脂肪变性的易感性，而不会增加肝和外周胰岛素抵抗的水平。rs738409 PNPLA3 G 等位基因与脂肪细胞大小的形态变化有关。
