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.
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.
|Gliniak, Christy M; Brown, J Mark; Noy, Noa (2017) The retinol-binding protein receptor STRA6 regulates diurnal insulin responses. J Biol Chem 292:15080-15093|
|Brown, J Mark; Hazen, Stanley L (2017) Targeting of microbe-derived metabolites to improve human health: The next frontier for drug discovery. J Biol Chem 292:8560-8568|
|Ferguson, Daniel; Zhang, Jun; Davis, Matthew A et al. (2017) The lipid droplet-associated protein perilipin 3 facilitates hepatitis C virus-driven hepatic steatosis. J Lipid Res 58:420-432|
|Schugar, Rebecca C; Shih, Diana M; Warrier, Manya et al. (2017) The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 Regulates Obesity and the Beiging of White Adipose Tissue. Cell Rep 19:2451-2461|
|Ding, Liang; Zhang, Lifang; Biswas, Sudipta et al. (2017) Akt3 inhibits adipogenesis and protects from diet-induced obesity via WNK1/SGK1 signaling JCI Insight 2:|
|Dasarathy, Srinivasan; Brown, J Mark (2017) Alcoholic Liver Disease on the Rise: Interorgan Cross Talk Driving Liver Injury. Alcohol Clin Exp Res 41:880-882|
|Brown, Amanda L; Mark Brown, J (2017) Critical roles for ?/? hydrolase domain 5 (ABHD5)/comparative gene identification-58 (CGI-58) at the lipid droplet interface and beyond. Biochim Biophys Acta 1862:1233-1241|
|Lord, Caleb C; Ferguson, Daniel; Thomas, Gwynneth et al. (2016) Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation. Cell Rep 16:939-949|
|Zhu, Weifei; Gregory, Jill C; Org, Elin et al. (2016) Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell 165:111-124|
|Warrier, Manya; Zhang, Jun; Bura, Kanwardeep et al. (2016) Sterol O-Acyltransferase 2-Driven Cholesterol Esterification Opposes Liver X Receptor-Stimulated Fecal Neutral Sterol Loss. Lipids 51:151-7|
Showing the most recent 10 out of 19 publications