Nutrigenetic intervention to reduce liver fat in Hispanics

Funder: NIMHD (RO1)
Funding Period: March 2016 for 4 years

The prevalence of pediatric non-alcoholic fatty liver disease (NAFLD) has doubled in the last 20 years and affects obese Hispanics most severely. We have found that 40% of obese Hispanic children and adolescents have a liver fat fraction above 5.5%, a clinical criteria for NAFLD diagnosis Over time, NAFLD can lead to cirrhosis, liver disease and eventually liver cancer. This increased susceptibility to high liver fat in Hispanics is due in part to a genetic predisposition based on the 50% frequency in this population of a C>G (Ile148Met) polymorphism in the PNPLA3 gene. Our prior studies, as well as recent studies in animal models, provide compelling evidence that the impact of the PNPLA3 variant on liver fat is exacerbated by high dietary sugar. Current approaches to reducing liver fat however are limited to general advice on weight loss and healthy eating but do not directly address the mechanism of excess fat accumulation in the liver, especially as it relates to this genetic predisposition in Hispanics. Therefore, the overall objective of this proposal is to develop innovative strategies, with potential for long-term sustainability, for addressing elevated liver fat in obese Hispanic children and adolescents based on genetic predisposition. We propose a randomized nutrigenetic clinical trial of dietary sugar reduction in children with clinically diagnosed NAFLD, to examine whether there are differential treatment responses based on PNPLA3 genotype. We will recruit 180 overweight and obese Hispanic children (12 – 18 years) with clinically verified NAFLD and randomize them to one of two 16-week interventions: 1) standard of care for healthy eating (control/placebo group); and 2) reduction of dietary sugars to 10% of total calories (treatment group). The following will be measured before and after intervention: total liver fat, liver fibrosis, visceral and subcutaneous abdominal adipose tissue volume by magnetic resonance imaging methods at 3T; total body fat by DEXA; plasma liver enzymes, fasting insulin, glucose, lipids, free fatty acids, and inflammatory markers, and insulin and glucose response to an oral glucose challenge. The hypotheses are: a) liver fat content and metabolic outcomes, such as lipids and inflammatory biomarkers, will show significantly greater improvements with sugar reduction relative to control; and b) a treatment*genotype interaction whereby the reduction in liver fat will be significantly greater in GG relative to CC/CG subjects. These results will provide efficacy data for a novel treatment strategy to reduce liver fat in obese Hispanic children and adolescents with NAFLD. Furthermore, this study has the potential to impact personalized dietary recommendations for treatment and prevention of NAFLD in Hispanics, as a function of genetic predisposition.