The long-term goal of our research is to reveal mechanisms underlying the naturally existing genetic variation of human fatty acid desaturase 1 (FADS1) gene in increasing the risk for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH); and to establish an evidence-based, personalized treatment strategy for NAFLD and NASH, with omega-3 (n-3) polyunsaturated fatty acids (PUFA) as a safe and inexpensive medication. The immediate goal of this application is to investigate the causal role of genetic variation of human fatty acid desaturase 1 (FADS1) gene in the development of NAFLD and NASH and in the response to n-3 PUFA supplementation in NAFLD. NAFLD and NASH are common chronic liver diseases causing significant morbidity and mortality, but with very limited treatment options. Many studies to date have demonstrated that n-3 PUFA deficiency is a risk factor for NAFLD. The levels of n-3 PUFAs in the blood and liver of NAFLD patients are significantly lower than in healthy individuals, and beneficial effects of n- PUFA supplementation in these patients have been increasingly recognized. However, recent clinical trials using n-3 PUFA to treat NAFLD yield mixed results, and this could be due to inter-patient difference in response to n-3 PUFA. Numerous studies have consistently demonstrated that blood n-3 PUFA levels in human population are significantly influenced by genetic variants in the FADS1 gene which encodes a key enzyme for converting dietary n-3 lipids into bioactive forms such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Individuals carrying the low-function alleles (>33% among major populations) of these variants have a much lower blood EPA and DHA levels than those with normal function alleles. Our recent studies demonstrated that these alleles markedly reduce FADS1 activity in human livers, leading to accumulation of saturated lipids and total fat, which also significantly increase the rik for NASH. We thus hypothesize that reduced FADS1 function increases the risk for NAFLD and NASH, and at the same time also increases an individual's sensitivity to n-3 PUFA treatment for NAFLD. We have performed preliminary studies in cell lines and have also established a murine model with Fads1 gene knockout. Our newly collected data with these models strongly support our hypotheses. In the current application, we propose to continue our success to focus on: 1) To establish the causal role and elucidate the mechanism of reduced FADS1 function in increasing the risk for NAFLD; 2) To test hypothesis that reduced FADS1 function leads to increased sensitivity to n-3 PUFA in ameliorating NAFLD; and 3) To validate the two relationships mentioned above in human NAFLD samples and primary hepatocytes. Our study will fill key knowledge gaps in this area and will provide important data needed to design and conduct genotype-stratified strategy for dietary or therapeutic or preventive intake of n-3 PUFA in treating NAFLD and beyond.

Public Health Relevance

Nonalcoholic fatty liver disease is a chronic disease affecting over 30% of the U.S. population and causing heavy societal burden. Our study has great potential to reveal a critical mechanism underlying the interaction between individual's genetic makeup and dietary nutrients intake in leading to the development of NAFLD. Our study also has potential to determine the NAFLD patients who are most suitable to receive omega-3 fatty acids (or fish oil) supplementation, which will eventually establish an effective, safe, inexpensiv and personalized therapeutic or preventive plan for NAFLD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK106540-03
Application #
9568077
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Doo, Edward
Project Start
2016-09-22
Project End
2021-07-31
Budget Start
2017-10-01
Budget End
2018-07-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Wayne State University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202