Effects of PNPLA3 on Liver Fat and Metabolic Profile in Hispanic Children and Adolescents

Abstract

OBJECTIVEA genome-wide study of adults identified a variant of PNPLA3 (rs738409) associated with ∼twofold higher liver fat. The purpose of this study was to examine the influence of PNPLA3 genotype on liver fat and other related metabolic outcomes in obese Hispanic children and adolescents.RESEARCH DESIGN AND METHODSThree hundred and twenty-seven Hispanics aged 8–18 years were genotyped for rs738409. One hundred and eighty-eight subjects had measures of visceral (VAT) and subcutaneous (SAT) adipose tissue volume and hepatic (HFF) and pancreatic (PFF) fat fraction by magnetic resonance imaging. One hundred and thirty-nine subjects did not have HFF measures but had extensive measures of insulin sensitivity and fasting lipids.RESULTSLiver fat in GG subjects was 1.7 and 2.4 times higher than GC and CC (11.1 ± 0.8% in GG vs. 6.6 ± 0.7% in GC and 4.7 ± 0.9% in CC; P < 0.0001), and this effect was observed even in the youngest children (8–10 years of age). The variant was not associated with VAT, SAT, PFF, or insulin sensitivity or other glucose/insulin indexes. However, Hispanic children carrying the GG genotype had significantly lower HDL cholesterol (40.9 ± 10.9 in CC vs. 37.0 ± 8.3 in CG vs. 35.7 ± 7.4 in GG; P = 0.03) and a tendency toward lower free fatty acid levels (P = 0.06).CONCLUSIONSThese results provide new evidence that the effect of the PNPLA3 variant is apparent in Hispanic children and adolescents, is unique to fat deposition in liver as compared with other ectopic depots examined, and is associated with lower HDL cholesterol.

Composite prognostic models across the non-alcoholic fatty liver disease spectrum: Clinical application in developing countries

“…The rs738409 variant similarly confers risk for increased histological severity dissociated from its effects on central obesity and IR [157,158] . Its pathogenic role in impaired lipid homeostasis as evidenced by a peripheral decrease in serum triglyceride, total and high-density lipoprotein cholesterol [159,160] is furthermore unmasked in the presence of increased visceral adiposity [161] and impaired glucose tolerance [162] , in addition to being modulated by lifestyle and dietary habits [161,163] . It has further been proposed that lipotoxicity and inflammatory stress resulting from impaired intra-hepatic lipid metabolism and free cholesterol deposition associated with PNPLA3 rs738409 activates dormant hepatic stellate cells (HSCs), leading to increased fibrogenesis.…”

The I148M Variant of PNPLA3 Reduces the Response to Docosahexaenoic Acid in Children with Non-Alcoholic Fatty Liver Disease

“…8,9 PNPLA3 is regulated by the lipogenic program and is involved in lipid metabolism in hepatocytes, and the I148M polymorphism alters the activity of this enzyme. 10,11 The I148M polymorphism influences liver damage and susceptibility to NASH early in life, 5,9,[12][13][14][15] synergizing with abdominal fat and carbohydrate intake. 16,17 Interestingly, there is some evidence that the I148M-NAFLD association is affected by the dietary N-6-PUFA/N-3-PUFA ratio, and it has been hypothesized that dietary supplementation with N-3-PUFA may reverse steatosis in carriers of the I148M polymorphism.…”

Which Method is Superior in the Diagnosis of Nonalcoholic Fatty Liver and Steatohepatatis in Children?

“…Association of 1148M variant with the disease progress to liver cancer and also shows the impact of this variant in the inflammation and exacerbation of the disease (60,63,65). Association between this variant, steatosis, and the levels of liver enzymes were observed in children with obesity in different races (67)(68)(69).…”