J. Mark Brown, PhD
Associate Staff
Director of Research, Center for Microbiome & Human Health
Email: [email protected]
Location: Cleveland Clinic Main Campus
Research
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. Our research is focused on lipid metabolic metabolic alterations driven by our commensal bacteria as well as our own human cells. All of our projects aim to translate basic discoveries into new therapeutic regimens for cardiometabolic disease.
Biography
Dr. Brown is Associate Staff in the Department of Cardiovascular & Metabolic Sciences and Director of Research in the Center for Microbiome & Human Health.
Education & Professional Highlights
Appointed
2013
Education & Fellowships
Fellowship - Wake Forest University Bowman Gray School of Medicine
Lipid Atherosclerosis
Winston-Salem, NC USA
2009
Medical Education - University of North Carolina at Greensboro
Cellular & Molecular Nutrition
Greensboro, NC USA
2004
Undergraduate - University of North Carolina at Greensboro
Nutrition/Diabetes
Greensboro, NC USA
2000
Research
My research is focused on the interrelationship between the diets we eat, microbe and host metabolism, and the development of chronic disease. We have three active research programs, and we are always looking for highly motivated young scientists to participate in our multidisciplinary training program.
Research Focus 1) Metaorganismal Endocrinology: Gut Microbe-Derived Hormones in Human Health & Disease.
Microbes resident in the human intestine represent a key transmissable factor contributing to a wide variety of human diseases. Here we are studying how gut microbes generate an array of small molecule metabolites that impact host physiology and disease. This line of investigation is studying the role of diet-microbe-host interactions in the context of obesity, diabetes, cardiovascular disease, and cancer.
Research Focus 2) Diet and Gene Interactions Driving the Progression of Non-Alcoholic Fatty Liver Disease (NAFLD) & Alcohol-Associated Liver Disease (AALD).
The progression of AALD and NAFLD to advanced fibrosis and end stage liver disease is driven by a combination of dietary and genetic factors. Here we are studying the interaction between metaorganismal nutrient metabolism (i.e. microbe and host metaboism) and host genetics (i.e. common and rare genetic variants), with the hopes of identifying new therapeutic strategies for those suffering from advanced liver disease.
Research Focus 3) Mechanisms by Which Nutrition & Obesity Drive Gastrointestinal (GI) Cancers.
Several common malignancies are associated with poor nutrition and obesity, particularly GI malignancies. In this series of projects, we are beginning to understand how metaorganismal nutrient metabolism impacts obesity and how this can be mechanistically tied to malignancies in the gut, liver, and kidneys.
Our Team
Selected Publications
View publications for J. Mark Brown, PhD
(Disclaimer: This search is powered by PubMed, a service of the U.S. National Library of Medicine. PubMed is a third-party website with no affiliation with Cleveland Clinic.)
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) Zhao, S., et al. (2014) alpha/beta hydrolase domain-6 accessible monoacylglycerol controls glucose-stimulated insulin secretion. Cell Metab. 19(6): 993-1007.
9) Zhu, W., et al. (2016) Gut microbial metabolite TMAO enhances platelet hypperreactivity and thrombosis risk. Cell 165: 111-124.
10) Lord, C.C., et al. (2016) Regulation of hepatic triacylglycerol metabolism by CGI-58 does not require ATGL co-activation. Cell Rep. 16, 939-949.
11) Schugar, R., et al. (2017) The TMAO-producing enzyme flavin-containing monooxygenase 3 regulates obesity and the beiging of what adipose tissue. Cell Rep. 19, 2451-2461.
12) Gromovsky, et al. (2017) Δ-5 fatty acid desaturase FADS1 impacts metabolic disease by balancing pro-inflammatory and pro-resolving lipid mediators. Arterioscler. Thromb. Vasc. Biol. 38(1): 218-231.
13) Roberts, A.B., et al. (2018) Development of a gut-microbe targeted non-lethal therapeutic to inhibit thrombosis potential without enhanced bleeding. Nat. Med. 24(9): 1407-1417.
14) Helsley, R.N., et al. (2019) Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease progression. Elife e49882.
15) Gimple, R.C., et al. (2019) Glioma stem cell specific super enhancer promotes polyunsaturated fatty acid synthesis to support EGFR signaling. Cancer Discov. 9(9): 1248-1267.
16) Zhou, H., et al. (2020) IL-1 induces mitochondrial translocation of IRAK2 Myddosome to suppress oxidative metabolism. Nat. Immunol. 21(10): 1219-1231.
17) Neumann, C.K.A., et al. (2020) MBOAT7-driven phosphatidylinositol remodeling promotes the progression of clear cell renal carcinoma. Mol. Metab. 34: 136-145.
18) Li, S., et al. (2020) Hepsin enhances liver metabolism and inhibits adipocyte browning in mice. Proc. Natl. Acad. Sci. USA 117(22): 12359-12367.
19) Orabi, D., et al. (2021) A novel surgical method for continuous intra-portal infusion of gut microbial metabolites. JCI Insight (In Press)
20) Tan, S.Z., et al. (2021) The obesity-dependent adipokine chemerin suppresses fatty acid oxidation to confer ferroptosis resistance. Cancer Discov. (In Press)
Careers
Research News
Machine learning crunches the numbers to more easily spot drug targets for diseases influenced by the gut microbiome.
The fellowship aims to nurture and develop early-career scientists.
Using pharmacological and genetic approaches, Dr. Brown found that silencing the gene MBOAT7 drove the development of non-alcoholic fatty liver disease in models fed a high-fat diet, and that obesity may contribute to this process by naturally suppressing MBOAT7 expression.
The grant will explore the critical link between microbial pathways and the development of cardio-metabolic diseases.