PNPLA3: A Determinant of Response to Low-Fructose Diet in Nonalcoholic Fatty Liver Disease

There is strong evidence supporting the association between nonalcoholic fatty liver disease and fructose consumption.1Vos M.B. et al.Hepatology. 2013; 57: 2525-2531Crossref PubMed Scopus (237) Google Scholar Fructose particularly drives hepatic de novo lipogenesis (DNL), which promotes lipotoxicity and steatohepatitis. Schwarz et al2Schwarz J.M. et al.Gastroenterology. 2017; 153: 743-752Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar have recently shown that isocaloric fructose restriction is associated with a reduction in liver fat and DNL in obese children. We note with interest the marked heterogeneity in participant responses to the low-fructose diet, with a significant proportion of participants exhibiting minimal or no change from baseline liver fat and DNL, despite achieving overall statistical significance. We postulate the role of PNPLA3 as a driver of this heterogeneity. The PNPLA3 p.Ile148Met (rs738409) polymorphism has been associated with progression of all stages of nonalcoholic fatty liver disease.3Romeo S. et al.Nature Genetics. 2008; 40: 1461-1465Crossref PubMed Scopus (2212) Google Scholar, 4Valenti L. et al.Hepatology. 2010; 52: 1274-1280Crossref PubMed Scopus (230) Google Scholar PNPLA3 is a significant modifier of liver fat and DNL; it is monosaccharide responsive, with increasing activity after a postprandial increase in insulin and is under control of carbohydrate response element-binding protein.5Smagris E. et al.Hepatology. 2015; 61: 108-118Crossref PubMed Scopus (243) Google Scholar In vitro and in vivo data have shown that the nonalcoholic fatty liver disease–associated variant is specifically important in the context of a high-fructose diet.6Li J.Z. et al.J Clin Invest. 2012; 122: 4130-4144Crossref PubMed Scopus (193) Google Scholar, 7Dubuquoy C. et al.J Hepatol. 2011; 55: 145-153Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar It is mechanistically plausible that patients harboring the PNPLA3-I48M variant would have higher baseline liver fat and have a more marked response to fructose restriction than those with wild-type PNPLA3. The frequency of PNPLA3 p.Ile148Met varies greatly between ethnicities. It is estimated at 0.55 in the Hispanic population and 0.14 in the African American population.8Lek M. et al.Nature. 2016; 536: 285-291Crossref PubMed Scopus (6551) Google Scholar We note that 20 of 25 Latino participants (80%) compared with only 5 of the 15 African American participants (33%) had elevated liver fat at baseline, which may be influenced by PNPLA3 genotype. We would be interested in the PNPLA3 polymorphism status of the participants in this study. There is widespread availability of laboratory assays for single nucleotide polymorphisms and these data would greatly support the conclusions of physiologic studies such as this. Therefore, we suggest that participants showing the greatest response to the fructose-restricted diet were those with PNPLA3 p.Ile148Met, whereas those lacking this variant may represent participants with minimal or no change from baseline. This is an important consideration for future studies exploring the role of dietary fructose on liver fat and DNL. Effects of Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis, and Insulin Kinetics in Children With ObesityGastroenterologyVol. 153Issue 3PreviewConsumption of sugar is associated with obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and cardiovascular disease. The conversion of fructose to fat in liver (de novo lipogenesis [DNL]) may be a modifiable pathogenetic pathway. We determined the effect of 9 days of isocaloric fructose restriction on DNL, liver fat, visceral fat (VAT), subcutaneous fat, and insulin kinetics in obese Latino and African American children with habitual high sugar consumption (fructose intake >50 g/d). Full-Text PDF