Obese and type 2 diabetic (T2DM) patients have a high incidence of nonalcoholic fatty liver disease (NAFLD). NAFLD is a continuum of chronic liver diseases ranging from benign steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis and primary hepatocellular cancer (HCC). Because of its strong association with the obesity epidemic, NAFLD is rapidly becoming a major public health concern in western societies. Surprisingly, there are no FDA approved NAFLD therapies; and current therapies treat the co-morbidities associated with NAFLD, viz., obesity, hyperglycemia, dyslipidemia, & hypertension. Our focus is on prevention of NAFLD and stopping its progression to NASH. We developed a preclinical Ldlr-/- mouse model of western diet (WD)-induced NASH. High fat-high sucrose diets, like the WD, have been implicated in promoting the obesity epidemic. Our preclinical model recapitulates the features seen in the metabolic syndrome (MetS)-NASH patient, i.e., obesity, hyperglycemia, dyslipidemia, hepatosteatosis, systemic and hepatic inflammation & hepatic fibrosis. The key premise of this application is that there is a causal link between hepatic C20-22 ?3 PUFA content and the onset and progression of NASH. This premise is based on the following research from our lab: 1) WD induced NASH is associated with hepatic depletion of C20-22 ?3 PUFA and bioactive ?3 PUFA-derived oxidized lipids (oxylipins); findings that parallel recent reports on NASH patients; 2) repletion of hepatic C20-22 ?3 PUFA and oxylipins with docosahexaenoic acid (DHA, 22:6,?3) supplementation prevents NASH and stops its progression; 3) New evidence shows that DHA attenuates WD-mediated induction of key NASH pathways [SREBP1, NF?B, TGF?-Smad3, Notch, Hedgehog (Hh) and osteopontin (Opn)]; and 4) more New evidence shows that ?6-PUFA-derived, but not ?3-PUFA-derived, oxylipins augment TGF? induction of a key fibrosis marker (smActin) in human hepatic stellate cells. Thus, DHA and its oxylipin derivatives regulate multiple NASH-linked pathways. We are well-positioned to uncover the metabolic and molecular basis for DHA-mediated suppression of NASH using our preclinical Ldlr -/- mouse model. Our goal is to provide the mechanistic foundation for the use of DHA in NASH therapy. We hypothesize that DHA attenuation of diet-induced NASH and fibrosis involves both direct and indirect mechanisms controlling major regulatory pathways (TGF?, Notch, HH & Opn) linked to NASH.
AIM 1 will use an in vivo time course approach to test the hypothesis that DHA will induce changes in hepatic membrane lipid composition and PUFA-derived oxylipins that precede changes in the expression/activity of signaling pathways linked to NASH & fibrosis.
AIM 2 will test the hypothesis that PUFA & oxylipins act directly on isolated liver cells (hepatocytes, macrophage & stellate cells) to regulate signaling pathways (TGF?, Notch, Hh & Opn) linked to NASH pathology.

Public Health Relevance

Non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH) have increased in parallel with central obesity and its prevalence is anticipated to increase as the obesity epidemic remains unabated. Our preclinical studies in mice have established that dietary docosahexaenoic acid (DHA, 22:6,?3) prevents the onset and blocks the progression of NASH. This application will define the mechanisms for the beneficial effect of DHA on liver health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK112360-03
Application #
9693228
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
2017-06-15
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Oregon State University
Department
Biology
Type
Schools of Public Health
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97331
Jump, Donald B; Lytle, Kelli A; Depner, Christopher M et al. (2018) Omega-3 polyunsaturated fatty acids as a treatment strategy for nonalcoholic fatty liver disease. Pharmacol Ther 181:108-125