Unravelling Mechanisms of Fructose vs Glucose Consumption in the Pathogenesis and Progression of NAFLD

Not Applicable

• Conditions: Non-alcoholic Fatty Liver Disease; Non-alcoholic Steatohepatitis
• Interventions: Dietary Supplement: Fructose; Dietary Supplement: Glucose

• Registration Number: NCT02075164
• Lead Sponsor: Prof. Michael Trauner, MD

Brief Summary

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from simple fatty liver over steatohepatitis (NASH) to liver cirrhosis and cancer (HCC) and is a major and increasing health problem affecting nearly 40% of the general population. Moreover, NAFLD is an important risk factor for progression of diabetes and atherosclerosis. However, the pathomechanisms determining disease progression are poorly understood. The overall aim of this project is to test the central hypothesis that excessive fructose consumption provides a multiple metabolic hit in the pathogenesis and progression of NAFLD/NASH by impairment of hepatic lipid homeostasis and mitochondrial function resulting in hepatic lipotoxicity with inflammasome activation and disturbed interorgan cross-talk among insulin sensitive tissues.

Detailed Description

To achieve these goals we will address the following specific hypotheses that

* Fructose-induced changes in lipid composition of hepatocellular stores determine lipotoxicity which may be associated with abnormalities in mitochondrial function, energy homeostasis, inflammasome activation and cellular injury in progression to NASH, effects which will be compared to glucose

* Non-invasive characterization of fructose (compared to glucose)-induced lipotoxic hepatic and extrahepatic metabolic risk profiles (lipid composition and energy metabolism) obtained by magnetic resonance spectroscopy (MRS) will identify patients with NASH

* Severity of fructose (compared to glucose)-induced lipotoxic lipid and adenosine triphosphate (ATP) derangements (identified by MRS) critically determines the degree of insulin resistance and abnormalities in hepatic glucose and lipid metabolism

* Compensatory hyperinsulinemia, secondary to skeletal muscle insulin resistance, may be a primary mechanism of hepatic lipotoxicity and progression to NASH

* Gender differences in the hepatic and systemic metabolic response to fructose are mediated by the impact of female sex hormones and their nuclear receptors on hepatic lipid metabolism, mitochondrial function and inflammasome activation.

* Age differences in the hepatic and systemic metabolic response to fructose are mediated by the impact of age related alterations on hepatic lipid metabolism and mitochondrial function.

These key hypotheses will be addressed by a translational research consortium including hepatologists, radiologists, physicists, endocrinologists and specialist in gender medicine allowing an integrated mechanistic approach to NAFLD. The strength of the current proposal comes directly from bridging basic science and clinical perspectives of different disciplines involved in the management of NAFLD, including cutting edge non-invasive technologies such as high field MRS metabolic profiling ('virtual metabolic liver biopsy') and mechanistic in vitro experiments. This project will provide novel mechanistic insights in the role of fructose as emerging hepatic 'toxin' in the pathogenesis and progression of NASH, as increasing health problem in Western society. Moreover, this study will clarify the impact of sex and gender on fructose-induced alterations in hepatic and systemic metabolism, providing a rational and scientific basis for future dietary interventions and regulatory actions.

Study Timeline

• Study Start: 2013-05
• Study First Submitted: 2014-02-06
• Study First Submitted QC: 2014-02-26
• Study First Posted: 2014-03-03
• Status Verified: 2020-09
• Last Update Submitted: 2020-09-04
• Last Update Posted: 2020-09-07
• Primary Completion: 2021-06
• Study Completion: 2021-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 56

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fructose	Fructose	Volunteers will be challenged with oral 150g Fructose per day for 56 days.
Glucose	Fructose	Volunteers will be challenged with oral 167g Fructose per day for 56 days.
Fructose	Glucose	Volunteers will be challenged with oral 150g Fructose per day for 56 days.
Glucose	Glucose	Volunteers will be challenged with oral 167g Fructose per day for 56 days.

Primary Outcome Measures

Name	Time	Method
Intrahepatic total fat and ipid composition assessed by Magnetic resonance spectroscopy	Healthy volunteers: Baseline, day 56 (8 weeks); NAFLD/NASH patients: Baseline	At baseline and on the last day of the study (day 56) Magnetic resonance spectroscopy will be carried out in healthy volunteers. (Prior and after double-blinded fructose versus glucose consumption for 8 weeks in each healthy volunteer).; In NAFLD and NASH patients Magnetic resonance spectroscopy will only be carried out at baseline, as this arms/groups do not undergo an oral fructose/glucose challenge.; Baseline measures between healthy volunteers and NAFLD/NASH groups/arms will be compared to assess differences between healthy individuals and patients.; Baseline and day 56 measures in healthy volunteers after fructose/glucose consumption will be compared to assess the influence of the dietary challenge.

Trial Locations

Locations (1)

Medical University of Vienna, General Hospital of Vienna Vienna, Vienna, Austria 1090; 🇦🇹 Vienna, Austria