Genetic-specific Effects of Fructose on Liver Lipogenesis

The primary goal of this study is to identify a set of genotypes that increase the risk for nonalcoholic fatty liver disease (NAFLD) and predispose individuals to increased de novo lipogenesis (DNL) and liver fat accumulation when exposed to fructose intake. The proposed goal will be achieved through the completion of following aims:

1. To determine the impact of prolonged exposure of fructose on hepatic lipid accumulation in Caucasian individuals with high and low genetic risk for NAFLD,
2. to determine the impact of acute exposure of fructose on hepatic DNL, and
3. to determine the relationship between markers of DNL, liver fat accumulation and serum concentrations of lipids, uric acid and liver function markers before and after the fructose challenge.

BACKGROUND AND RATIONALE Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in liver cells not caused by alcohol. A leading cause of chronic liver disease in the US, NAFLD represents a group of disorders including steatosis, nonalcoholic steatohepatitis with fibrosis. It has substantially risen in prevalence over the last two decades with the estimated prevalence being 20% among US adults and 25% in young adults (18-39 years). Over 64 million individuals are believed to have NAFLD with annual medical costs rising to more $100 billion. More common in individuals who are obese or diabetic and/or have metabolic syndrome, NAFLD has been associated with increased cirrhosis, liver-related mortality and hepatocellular carcinoma.

Both genetic and environmental, including nutritional, factors contribute to the onset and progression of NAFLD. Increased consumption of sugar-sweetened, fructose-rich beverages has been linked to NAFLD. Fructose, commonly found in soft drinks, fruit juices and energy drinks, affects many metabolic processes, foremost being an increase in fat accumulation in the liver and hence, NAFLD. Genome-wide and candidate gene studies have identified several genes associated with NAFLD. However, none of these studies have shown the cumulative effects of single nucleotide polymorphisms (SNPs) on changes in liver fat when exposed to fructose. The results from this study can be extrapolated to larger cohorts and other ethnicities and are therefore, expected to lay the foundation for developing personalized nutritional plans.

Eligibility Criteria:
Inclusion Criteria:

1. Subjects 12 - 40 years
2. No history of alcohol abuse (\> 7 drinks per week)
3. History of fructose intake of \< 14 drinks per week
4. Caucasian ethnicity
5. BMI \> 25kg/m² - 32kg/m² or 85th -99th percentile but otherwise healthy

Exclusion Criteria:

1. ages \< 12 and \> 40 years
2. Pregnant/lactating
3. known alcohol abuse or fructose intake \> 14 drinks per week
4. not of Caucasian ethnicity
5. glucose levels \> 100 mg/dL if fasting, \> 140mg/dL if within 2 hours post meal and \> 200 mg/dL if random sample
6. taking anti-hypertensive, anti-diabetic, uric acid and/or lipid-lowering medications
7. known diagnosis of diabetes, fructose intolerance, chronic kidney disease, NAFLD or any liver-related disease, hypertriglyceridemia, polycystic ovary syndrome, hypothyroidism, obstructive sleep apnea, hypopituitarism and hypogonadism
8. BMI \< 25kg/m² or \> 32 kg/m² or \< 85th or \> 99th percentile
9. Liver fat fraction \>5% as per baseline MRI scan