Genetic and dietary determinants of nonalcoholic fatty liver disease in Hispanic children

The purpose of this dissertation is to summarize our recent findings that have examined dietary, genetic and inflammatory factors that contribute to fat accumulation and nonalcoholic fatty liver disease (NAFLD) in Hispanic children. In addition, this dissertation discusses how some of these contributions to liver fat may vary across the population in terms of ethnic-specific effects and future treatments that may result from the findings presented. ❧ Recent genome wide studies have identified several polymorphisms that contribute to increased liver fat accumulation, with some of these genes relating to dietary carbohydrate and sugar consumption. In particular, a variant of the PNPLA3 gene, which is highly prevalent in Hispanics, contributes to excessive liver fat beginning at a young age, especially in the context of high sugar consumption. We show that a genetic risk score comprised of variants associated with liver fat improve detection of NAFLD when added to current clinical measures. Additionally, dietary carbohydrate, and especially fructose, has been shown to contribute to increased liver fat accumulation due to the lipogenic potential of fructose during liver metabolism. We present data that demonstrates certain beverages amongst sodas and juices contain higher concentrations of fructose than previously thought, suggesting population estimates of fructose consumption in children and adults are underestimated. Lastly, we present recent finding suggesting that inflammation and fibrosis in the subcutaneous adipose tissue of children may impact liver disease progression and increase risk for type 2 diabetes. ❧ Dietary sugar contributes to liver fat accumulation, with this being explained by de novo lipogenesis from fructose in the liver. Certain genetic factors, including PNPLA3, GCKR and APOC3 contribute to increased liver fat accumulation, with these effects being manifested at an early age. Hispanics in particular are at elevated risk for liver fat accumulation due to the higher frequency of genetic variants such as PNPLA3 and GCKR as well as an interaction between the PNPLA3 and dietary sugar. Additionally, adipose inflammation caused by the obese state may incur elevated risk for liver disease and type 2 diabetes. The summation of these factors represents, and potentially explains, the added risk and high prevalence of NAFLD among the Hispanic pediatric population.