Department of Cellular and Molecular Medicine
Jonathan Mark Brown, PhD
Lerner Research Institute
9500 Euclid Avenue
Cleveland, Ohio 44195
Phone: (216) 444-8340
Fax: (216) 444-9404
My research is focused on the interrelationship between lipid metabolism and the development of chronic diseases such as obesity, diabetes, and atherosclerosis. We have three active research programs, and we are always looking for highly motivated young scientists to participate in our multidisciplinary training program.
Project 1) Mechanism Regulating Trans-Intestinal Cholesterol Excretion (TICE). The process of reverse cholesterol transport (RCT) has long been thought require intact biliary secretion. However, our work has revealed a novel RCT pathway that is independent of biliary secretion. We are currently probing mechanisms driving this novel pathway, and testing novel therapeutics targeting this pathway for protection against atherosclerosis.
Project 2) Metaorganismal Endocrinology: Gut Microbe-Derived Hormones in Driving Cardiometabolic Disease.Microbesresident in the human intestine represent a key factor contributing to cardiometabolic disease. Here we are studying a metaorganismal endocrine axis by which gut microbial metabolism ofnutrients common in high fat diets (phosphatidylcholine, choline, and L-carnitine) results in the production ofnovel microbe-derived hormones that impact obesity and insulin sensitivity in the host.
Project 3) Alpha Beta Hydrolase Domain (ABHD) Proteins in Metabolic Disease. We are functionally annotatinga family of proteins known as alpha/beta hydrolase domain (ABHD) containing proteins. These proteins are highly conserved lipid metabolizing enzymes, and mutations in several of these proteins have been implicated in inherited inborn errors in lipid metabolism. These studies are uncovering novel roles for ABHD enzymes in the development of obesity, hepatic steatosis, type II diabetes, and cancer.
In other words ...
A long-term goal of my laboratory is to understand the fundamental pathways that dictate how our bodies make, store, and degrade fats or lipids. Most chronic diseases that we are faced with today like coronary heart disease, obesity, diabetes, cancer, and even infectious disease are driven by underlying alterations in lipid metabolism. We are making exciting new discoveries that we aim to translate into new therapeutic regimens for metabolic disease.
1) Temel, et al. (2010) Biliary sterol secretion is not required for macrophage reverse cholesterol transport. Cell Metab. 12(1): 96-102.
2) Lord, C.C., et al. (2012) CGI-58/ABHD5-derived signaling lipids regulate systemic inflammation and insulin action. Diabetes 61(2): 355-363.
3) Cantley, J.L., et al. (2013) CGI-58 knockdown sequesters diacylglycerols in lipid droplets, preventing DAG-mediated PKCε translocation to the plasma membrane and hepatic insulin resistance. Proc. Natl. Acad. Sci USA 110(5): 1869-1874.
4) Koeth, R.A., et al. (2013) Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19(5): 576-585.
5) Thomas, G., et al. (2013) The serine hydrolase ABHD6 is a critical regulator of the metabolic syndrome. Cell Rep. 5(2): 508-520.
6) Warrier, M., et al. (2015) The TMAO-generating enzyme flavin monooxygenase 3 is a central regulator of cholesterol balance. Cell Rep. 10: 1-13.
7) Schreiber, R., et al. (2015) Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause reisstance to HFD-induced obesity. Proc. Natl. Acad. Sci. USA 112(5): 13850-13855.
8) Prisbasnig, M.A., et al., (2015) alpha/beta hydrodrolase domain-containing 6 (ABHD6) degrades teh late endosomal/lysosomal lipid bis(monoacylglycerol)phosphate. J. Biol. Chem. 290(50): 29869-29881.
9) Zhao, S., et al. (2014) alpha/beta hydrolase domain-6 accessible monoacylglycerol controls glucose-stimulated insulin secretion. Cell Metab. 19(6): 993-1007.
10) Zhu, W., et al. (2016) Gut microbial metabolite TMAO enhances platelet hypperreactivity and thrombosis risk. Cell (In Press)
*** Search for more Brown laboratory publicaitons: http://www.ncbi.nlm.nih.gov/pubmed/?term=j+mark+brown