Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, which includes simple steatosis (NAFL) and non-alcoholic steatohepatitis (NASH). NAFLD not only causes liver dysfunctions but also induces extra-hepatic complications. Accumulating data indicate that cardiovascular disease (CVD) is the major cause of deaths in NAFLD patients. So far, the mechanism underlying the development of NAFLD is poorly understood. In addition, it is unclear why NAFLD patients have increased incidence of CAD. Forkhead box A3 (FOXA3) is a transcription factor whose function in lipid or lipoprotein metabolism has not been established. Our preliminary studies show that hepatic FOXA3 expression is markedly reduced under common metabolic stress. Using over-expression or knockdown approaches, we show that hepatic FOXA3 regulates hepatic lipid and plasma HDL levels as well as the expression of HDL-associated proteins. These novel data suggest that dysregulation of hepatic FOXA3 may play an important role in the pathogenesis of both NAFLD and CVD. To test this hypothesis, we will use both gain- and loss-of-function approaches. Completion of the proposed studies may uncover a novel role of hepatic FOXA3 in the development of NAFLD and atherosclerosis and may offer novel insights into the mechanism by which NAFLD is a risk factor for CAD.

Public Health Relevance

Relevance: NAFLD is the most common chronic liver disease in developed countries and cardiovascular disease is the major cause of deaths in NAFLD patients. Completion of the proposed studies will help determine the role of hepatic FOXA3 in the development of both NAFLD and atherosclerosis, and may lead to a new strategy for treatment of these two common and causatively related diseases. Thus, this project is highly relevant to human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK118805-01A1
Application #
9686215
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Doo, Edward
Project Start
2019-04-01
Project End
2023-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Northeast Ohio Medical University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
077779882
City
Rootstown
State
OH
Country
United States
Zip Code
44272