To define the mechanism(s) by which fructose may contribute to nonalcoholic fatty liver disease (NAFLD) progression and assess whether such factors can be measured using magnetic resonance (MR) biomarkers and modified with dietary fructose restriction. Background: NAFLD is a major public health concern which is anticipated to surpass the morbidity and mortality of other forms of chronic liver disease by 2020. Both the prevalence and severity of NAFLD have been associated with increased consumption of fructose. We have reported that increased fructose consumption is associated with decreased hepatic steatosis, liver injury (necroinflammation and hepatocyte ballooning) and fibrosis in a dose-dependent manner. The unique metabolism of fructose, one which depletes hepatic ATP, increases uric acid, and worsens features of insulin resistance, is a potential mechanism that may account for fructose-related liver injury in NAFLD. Given the changes which occur with fructose exposure, fructose is an ideal diagnostic "tool" by which to induce and/or amplify changes in quantitative MR-based biomarkers and "target" for dietary intervention studies for the treatment of NAFLD. Hypothesis: We hypothesize that fructose is a risk factor for hepatic steatosis, steatohepatitis, and advanced fibrosis and that acute and chronic fructose exposure will worsen the metabolic, energy homeostatic and associated MR-based biomarkers features of NAFLD. Further, we hypothesize that dietary fructose restriction will improve these metabolic and energy homeostatic derangements. Approach: Quantitative MR biomarkers of hepatic metabolites and energy homeostasis will be evaluated before, during, and after acute/chronic fructose challenges. We will characterize the pathophysiologic changes which occur with fructose exposure using multi-parametric analysis of MRI and 1H and 31P and spectroscopic imaging data to measures of metabolism and energy homeostasis and relate these to the histologic features of NAFLD. Impact: This work addresses the following significant gaps in knowledge: 1) whether acute and chronic fructose exposure alters metabolism, energy homeostasis, and is associated with liver injury in patients with/without NAFLD and 2) whether modification of fructose consumption could improve the clinical and pathologic features of NAFLD. The successful completion of the proposed studies will provide novel and clinically relevant information regarding the pathophysiologic and pathologic mechanism underlying fructose-related liver injury in humans. The proposed studies will be the first to correlate the dynamic measures of non-invasive MR-based biomarkers and energy homeostasis with the clinical, metabolic and histologic features of NAFLD. The integration of these biomarkers in a cross-sectional and longitudinal study will characterize their use for measuring changes associated with fructose-related liver injury and facilitate the development of non-invasive biomarkers for NAFLD diagnosis and progression.

Public Health Relevance

The goal of this project is to define the mechanism(s) by which fructose may contribute to nonalcoholic fatty liver disease (NAFLD) progression, assess whether such factors can be measured using dynamic MRI/MRS biomarkers and whether these factors can be modified with dietary fructose restriction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093568-03
Application #
8604391
Study Section
Special Emphasis Panel (ZRG1-DTCS-U (81))
Program Officer
Laughlin, Maren R
Project Start
2012-01-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
3
Fiscal Year
2014
Total Cost
$282,603
Indirect Cost
$102,601
Name
Duke University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705