Dysregulation of cholesterol balance contributes significantly to coronary heart disease (CHD), the leading cause of death in the United States. Given that mammals cannot catabolize cholesterol, a multi-organ process known as reverse cholesterol transport (RCT) has evolved to facilitate cholesterol excretion into the feces. Although the process of RCT is well appreciated to protect against the development of CHD, the long-standing theoretical model for RCT has recently been called into question. Recently, we have demonstrated that RCT can proceed in the absence of biliary secretion through a novel pathway known as transintestinal cholesterol excretion (TICE), which has challenged the field to significantly modify the conceptual framework of RCT. Studies proposed here will comprehensively analyze the role of a new player in RCT (Flavin Monooxygenase 3, FMO3), that we have identified using unbiased screening approaches in mouse models of altered TICE. Recently, FMO3-driven enzymatic conversion of gut microbiota-derived trimethylamine (TMA) to trimethylamineoxide (TMAO) has been strikingly associated with CHD risk in humans. Our studies will examine the signaling role for FMO3's substrate (TMA) and product (TMAO) in regulating biliary and non-biliary RCT, and how this relates to atherosclerosis progression and regression. Our proposed studies have strong potential to provide preclinical evidence that FMO3 is the first bona fide drug target for specifically stimulating the TICE pathway, and will provide evidence whether stimulation of TICE is atheroprotective. Collectively, these studies have potential to lead to novel therapies for the prevention and/or treatment of CHD, and to transform our current theoretical model of RCT.

Public Health Relevance

Data obtained from these studies are expected to define novel molecular mechanisms regulating a recently described pathway regulating reverse cholesterol transport (RCT) known as transintestinal cholesterol efflux (TICE). By elucidating the molecular mechanisms regulating the TICE pathway this project has the potential to have broad impact on future drug discovery programs for CHD prevention in humans by advancing our mechanistic understanding of both biliary and non-biliary RCT.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL122283-01
Application #
8670857
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Ershow, Abby
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$396,250
Indirect Cost
$146,250
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Hazen, Stanley L; Brown, J Mark (2014) Eggs as a dietary source for gut microbial production of trimethylamine-N-oxide. Am J Clin Nutr 100:741-3