Genetic-specific Effects of Fructose on Liver Lipogenesis

Not Applicable

Completed

• Conditions: NAFLD
• Interventions: Other: Sugar drink

• Registration Number: NCT03783195
• Lead Sponsor: University of North Carolina, Chapel Hill

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2018-12-17
• Study First Submitted QC: 2018-12-19
• Study First Posted: 2018-12-20
• Study Start: 2019-01-25
• Primary Completion: 2023-04-25
• Study Completion: 2023-04-25
• Status Verified: 2023-05
• Disposition First Posted: 2023-06-22
• Disposition First Submitted: 2024-03-28
• Results First Submitted: 2024-05-23
• Results First Submitted QC: 2024-09-27
• Last Update Submitted: 2024-09-27
• Results First Posted: 2024-10-23
• Last Update Posted: 2024-10-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 15

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
High GRS group	Sugar drink	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.
Low GRS group	Sugar drink	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.

Primary Outcome Measures

Name	Time	Method
Mean Change in AUC of Serum Very Low Density Lipoprotein-triglycerides (VLDL-TG)	between week 0 (Baseline) and week 3	Area under curve (AUC) (mg\*hr/dl) of serum VLDL-TG for baseline and 3hr time points at week 0 and Week 3.
Mean Change in Liver Fat Content Based on Elastography	between week 0 (Baseline) and week 3	Elastography (Fibroscan) will be used to measure changes in liver fat.
Mean Percent Change in Liver Fat Content Based on MRI	between week 0 (Baseline) and week 3	Magnetic resonance imaging (MRI) will be used to measure changes in liver fat (% change in fat fraction).
Mean Change in Serum Concentrations of Very Low Density Lipoprotein-triglycerides (VLDL-TG)	between week 0 (Baseline) and week 3	VLDL-TG measurement in serum (mg/dl) at week 0 and Week 3.

Secondary Outcome Measures

Name	Time	Method
Mean Changes in Serum Concentrations of Uric Acid	between week 0 (Baseline) and week 3	Fasting concentrations of serum uric acid (ng/ml) will be measured at week 0 and week 3
Mean Changes in AUC of Serum Uric Acid	between week 0 (Baseline) and week 3	Area under curve (AUC) (ng\*hr/ml) of serum uric acid for baseline and 3hr time points at week 0 and Week 3.
Mean Change in AUC of Serum LDL Cholesterol	Week 0 (baseline) and week 3	Area under curve (AUC) (mg\*hr/dl) of serum LDL cholesterol for baseline and 3hr time points at week 0 and Week 3.
Mean Change in Serum Concentrations of Total Cholesterol	between week 0 (Baseline) and week 3	Fasting serum concentrations of total cholesterol (mg/dl) will be measured at week 0 and week 3
Mean Change in AUC of Serum Total Cholesterol	week 0 and week 3	Area under curve (AUC) (mg\*hr/dl) of serum total cholesterol for baseline and 3hr time points at week 0 and Week 3.
Mean Change in Serum Concentrations of Liver Function Marker (Aspartate Transaminase-AST).	between week 0 (Baseline) and week 3	Serum concentrations of serum AST will be measured at week 0 and week 3
Mean Change in AUC of Serum Aspartate Transaminase (AST).	between week 0 (Baseline) and week 3	Area under curve (AUC) (IU\*hr/L) of serum AST for baseline and 3hr time points at week 0 and Week 3.
Mean Change in Serum Concentrations of Liver Function Marker (Alanine Transaminase- ALT).	between week 0 (Baseline) and week 3	Fasting concentrations of serum ALT (nmol) will be measured at week 0 and week 3
Mean Change in AUC of Serum Alanine Transaminase (ALT)	between week 0 (Baseline) and week 3	Area under curve (AUC) (nmol/hr) of serum ALT for baseline and 3hr time points at week 0 and Week 3.
Mean Change in Serum Concentrations of Triglycerides	between week 0 (Baseline) and week 3	Fasting concentrations of serum triglycerides (mg/dl) will be measured at week 0 and 3
Mean Change in AUC of Serum Triglycerides	between week 0 (Baseline) and week 3	Area under curve (AUC) (mg\*hr/dl) of serum VLDL-TG for baseline and 3hr time points at week 0 and Week 3.
Mean Change in Serum Concentrations of HDL Cholesterol	between week 0 (Baseline) and week 3	Fasting concentrations of serum HDL cholesterol (mg/dl) will be measured at week 0 and week 3.
Mean Change in AUC of Serum HDL Cholesterol	between week 0 (baseline) and week 3	Area under curve (AUC) (mg\*hr/dl) of serum HDL cholesterol for baseline and 3hr time points at week 0 and Week 3.
Mean Change in Serum Concentrations of LDL Cholesterol	between week 0 (Baseline) and week 3	Fasting concentrations of serum LDL cholesterol (mg/dl) will be measured.at week 0 and week 3
Mean Change in Serum Concentrations of Liver Function Marker (Alkaline Phosphatase-ALP)	between week 0 (Baseline) and week 3	Fasting concentrations of serum ALP (nmol) will be measured at week 0 and week3
Mean Change in AUC of Serum Alkaline Phosphatase (ALP)	between week 0 (Baseline) and week 3	Area under curve (AUC) (nmol/hr) of serum ALP for baseline and 3hr time points at week 0 and Week 3.
Mean Change in Serum Concentrations of Liver Function Marker (Gamma Glutamyl Transpeptidase-GGT)	between week 0 (Baseline) and week 3	Serum concentrations of GGT will be measured at week 0 and week 3
Mean Change in AUC of Serum Gamma Glutamyl Transpeptidase (GGT)	between week 0 (Baseline) and week 3	Area under curve (AUC) (IU\*hr/dl) of serum VLDL-TG for baseline and 3hr time points at week 0 and Week 3.

Trial Locations

Locations (1)

UNC Nutrition Research Institute; 🇺🇸 Kannapolis, North Carolina, United States