Moreover, the study conclusions only pertain to children with both steatosis and elevated liver enzymes. Further studies will be required to determine the prognosis of children with severe

steatosis who are homozygous for the risk allele and yet do not have elevated liver enzymes. In the same issue, Santoro et al.10 examined the effects of the PNPLA3-I148M variant on fuel homeostasis and adipocyte size in an ethnically diverse, obese pediatric population. Although the study by Santoro et al.10 Ku-0059436 mw was smaller (n = 85), the association between hepatic triglyceride content and the PNPLA3-I148M variant was detected in their population. Because liver biopsies were performed in selleck compound just six subjects, the relationship between the risk allele and hepatic pathology could not be examined. Consistent with the original reports,6, 14 no association was found between the variant and metabolic indicators of insulin resistance. Specifically, no differences in hepatic glucose production rate or peripheral glucose disposal were detected by hyperinsulinemic euglycemic clamp studies. This finding confirms and further strengthens the mechanistic dissociation between hepatic triglyceride content and insulin resistance. Although hepatic triglyceride content is strongly associated with insulin

resistance, the insulin resistance is not a direct consequence of the increase in hepatic triglyceride content. This study also probed the effect of the variant on indices of adipose tissue metabolism. No genotype-dependent differences were found in body fat content or distribution, or in the rate of lipolysis, as assessed by glycerol turnover. The size of adipocytes measured in 18 subjects revealed a small reduction in median adipocyte size in carriers (∼92

versus ∼80 μm; P = 0.05). Given the small number of subjects analyzed (just 11 carriers and 7 controls), this finding must be interpreted with caution, especially because the PNPLA3 genotype is not associated with adiposity or body fat distribution. MCE The physiological function of PNPLA3 is enigmatic, and the mechanistic link between the I148M variant and liver disease remains unclear. PNPLA3 is associated with the endoplasmic reticulum and with lipid droplets in hepatoctyes (Fig. 1).15 The enzyme exhibits both triglyceride hydrolase and transacylation activity in vitro,16 so it can promote either triglyceride catabolism or anabolism. The substitution of methionine for isoleucine at residue 148 disrupts triglyceride hydrolysis by the enzyme,15 suggesting that PNPLA3-I148M may be a loss-of-function mutation (Fig. 1A). However, ablation of PNPLA3 in two different strains of mice (C57BL/6J and Lepob/ob) yielded no significant increase in hepatic lipid content or serum aminotransferase levels under a variety of dietary conditions.