Genetic-specific Effects of Fructose on Liver Lipogenesis

Study Overview
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Brief Summary
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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: To determine the impact of prolonged exposure of fructose on hepatic lipid accumulation in Caucasian individuals with high and low genetic risk for NAFLD, to determine the impact of acute exposure of fructose on hepatic DNL, and 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.

Detailed Description
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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.

Official Title
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Genetic-specific Effects of Fructose on Liver Lipogenesis

Conditions
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NAFLD

Intervention / Treatment
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* Other: Sugar drink


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects 12 - 40 years No history of alcohol abuse (> 7 drinks per week) History of fructose intake of < 14 drinks per week Caucasian ethnicity BMI > 25kg/m² - 32kg/m² or 85th -99th percentile but otherwise healthy Exclusion Criteria: ages < 12 and > 40 years Pregnant/lactating known alcohol abuse or fructose intake > 14 drinks per week not of Caucasian ethnicity glucose levels > 100 mg/dL if fasting, > 140mg/dL if within 2 hours post meal and > 200 mg/dL if random sample taking anti-hypertensive, anti-diabetic, uric acid and/or lipid-lowering medications 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 BMI < 25kg/m² or > 32 kg/m² or < 85th or > 99th percentile Liver fat fraction >5% as per baseline MRI scan

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants are assigned to high genetic risk score group in parallel to low genetic risk score group
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High GRS group<br>This group consists of individuals who are in the highest quartile of the genetic risk score (GRS) and will ingest one sugar drink (equal to 2 soft drinks) per day for 3 weeks. The GRS is computed by adding the number of alleles that increase the risk for liver lipogenesis or fatty liver. | Other: Sugar drink<br>* A sugar drink made with 1.2 g/kg body weight of added sugar( 0.75g/kg body weight of fructose + 0.45g/kg body weight of glucose) and 24oz water<br>|
| Experimental: Low GRS group<br>This groups consists of individuals who are in the lowest quartile of the genetic risk score (GRS) and will ingest one sugar drink (equal to 2 soft drinks) per day for 3 weeks. The GRS is computed by adding the number of alleles that increase the risk for liver lipogenesis or fatty liver. | Other: Sugar drink<br>* A sugar drink made with 1.2 g/kg body weight of added sugar( 0.75g/kg body weight of fructose + 0.45g/kg body weight of glucose) and 24oz water<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver fat content (%) | Magnetic resonance imaging (MRI) and transient elastography (Fibroscan) will be used to measure changes in liver fat. | at week 0 and 3 | 
| Serum concentrations of low density lipoprotein-triglycerides (VLDL-TG) | VLDL-TG measurement in serum (mg/dl) | 0, 1 and 3 hours at week 0 and week 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum concentrations of triglycerides | Fasting concentrations of serum triglycerides (mg/dl) will be measured. | at week 0 and week 3 | 
| Serum concentrations of HDL cholesterol | Fasting concentrations of serum HDL cholesterol (mg/dl) will be measured. | at week 0 and week 3 | 
| Serum concentrations of LDL cholesterol | Fasting concentrations of serum LDL cholesterol (mg/dl) will be measured. | at week 0 and week 3 | 
| Serum concentrations of total cholesterol | Fasting serum concentrations of total cholesterol (mg/dl) will be measured. | at week 0 and week 3 | 
| Serum concentrations of uric acid | Fasting concentrations of serum uric acid (ng/ml) will be measured. | at week 0 and week 3 | 
| Serum concentrations of liver function marker (Alanine transaminase- ALT). | Fasting concentrations of serum ALT (IU/L) will be measured. | at week 0 and week 3 | 
| Serum concentrations of liver function marker (Aspartate transaminase-AST). | Fasting concentrations of serum AST (IU/L) will be measured. | at week 0 and week 3 | 
| Serum concentrations of liver function marker (Alkaline phosphatase-ALP) | Fasting concentrations of serum ALP (IU/L) will be measured. | at week 0 and week 3 | 
| Serum concentrations of liver function marker (Gamma glutamyl transpeptidase-GGT) | Fasting concentrations of serum GGT will be measured. | at week 0 and week 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucose, Fructose, Fatty-liver, Polymorphisms, Imaging, Fibroscan