Mitchell A. Lazar, MD, PhD

faculty photo
Sylvan H. Eisman Professor of Medicine
Department: Medicine

Contact information
12-102 Smilow Center for Translational Research
3400 Civic Center Boulevard / 5160
Philadelphia, PA 19104-5160
Office: (215) 898-0198
Fax: (215) 898-5408
S.B. (Chemistry)
Massachusetts Institute of Technology, 1976.
Ph.D. (Neuroscience)
Stanford Univerity, 1981.
Stanford Univerity, 1982.
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Description of Research Expertise

Research Interests
Epigenomic regulation of transcription and metabolism by nuclear receptors; mechanism of obesity-associated insulin resistance and diabetes; circadian regulation of metabolism

Key words: diabetes, endocrinology, epigenomics, nuclear receptors, circadian rhythms

Description of Research
The Lazar laboratory is studying the transcriptional and epigenomic regulation of metabolism. We are particularly focused on the role played by nuclear receptors (NRs). In the absence of ligand, NRs bind to DNA and function as potent transcriptional repressors by recruiting corepressor complexes that include the chromatin modulating enzyme histone deacetylase 3 (HDAC3). We are studying the tissue-specific and physiological roles of the corepressor complexes using by combining genomic, genetic, proteomic, and bioinformatics, and metabolic phenotyping approaches. We are especially interested in the circadian NR Rev-erbα, which utilizes the corepressor complex to potently repress transcription. Rev-erbα is a key repressive component of the circadian clock that senses heme levels to coordinate metabolism and biological rhythms. We are also studying PPARγ, a nuclear receptor that is a master regulator of adipocyte (fat cell) differentiation. Ligands for PPARγ have potent antidiabetic activity, and thus PPARγ represents a key transcriptional link between obesity and diabetes. The molecular, cellular, and integrative biology of these factors are being studied in mouse and human cell lines as well as in mouse knockin and knockout models. We also have discovered resistin, a novel hormone and target of PPARγ that is made and secreted by fat cells in rodents and by macrophages in humans. We have demonstrated that resistin regulates insulin responsiveness, and are now using mice humanized for resistin to test the hypothesis that resistin links metabolism to inflammation in human metabolic diseases.

Rotation Projects for 2013-2014
There are numerous potential projects that I would be pleased to discuss in person.

Lab personnel:
David Steger, Ph.D. (Research Assistant Professor)
Fenfen Wang (Graduate Student)
Sonia Step (Graduate Student)
Ray Soccio, M.D., Ph.D. (Post-doc)
Zheng Sun, Ph.D. (Post-doc)
Joanna DiSpirito, Ph.D. (Post-doc)
Logan Everett, Ph.D. (Post-doc)
Jennifer Jager, Ph.D. (Post-doc)
Zachary Gerhart-Hines, Ph.D. (Post-doc)
Bin Fang, Ph.D. (Post-doc)
Jill Marinis, Ph.D. (Post-doc)
Sean Armour, Ph.D. (Post-doc)
Lei Zhou, Ph.D. (Post-doc)
Matthew Emmett (Graduate Student)
Jarrett Remsberg (Graduate Student)
Yuxiang Zhang (Graduate Student)
Samar Shah (Graduate Student)
Erika Briggs (Research Specialst)
Lindsey Peed(Research Specialist)
Eric Chen (Research Specialist)
Cristina Lanzillotta (Research Specialist)
Joe Weaver (Lab Manager)

Selected Publications

Sun Z, Feng D, Fang B, Mullican SE, You SH, Lim HW, Everett LJ, Nabel CS, Li Y, Selvakumaran V, Won KJ, Lazar MA.: Deacetylase-Independent Function of HDAC3 in Transcription and Metabolism Requires Nuclear Receptor Corepressor. Mol Cell. 52(6): 769-82, Dec 2013.

Alenghat T, Osborne LC, Saenz SA, Kobuley D, Ziegler CG, Mullican SE, Choi I, Grunberg S, Sinha R, Wynosky-Dolfi M, Snyder A, Giacomin PR, Joyce KL, Hoang TB, Bewtra M, Brodsky IE, Sonnenberg GF, Bushman FD, Won KJ, Lazar MA, Artis D: Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis. Nature 504(7478): 153-7, Dec 2013.

Mullican SE, Dispirito JR, Lazar MA.: The orphan nuclear receptors at their 25-year reunion. J Mol Endocrinol. Page: [Epub ahead of print] Nov 2013.

Sun Z, Feng D, Fang B, Mullican SE, You SH, Lim HW, Everett LJ, Nabel CS, Li Y, Selvakumaran V, Won KJ, Lazar MA.: Deacetylase-Independent Function of HDAC3 in Transcription and Metabolism Requires Nuclear Receptor Corepressor. Mol Cell. Nov 2013 Notes: 2013 Nov 19. pii: S1097-2765(13)00788-0. doi: 10.1016/j.molcel.2013.10.022. [Epub ahead of print]

Schupp M, Chen F, Briggs ER, Rao S, Pelzmann HJ, Pessentheiner AR, Bogner-Strauss JG, Lazar MA, Baldwin D, Prokesch A.: Metabolite and transcriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissues. BMC Genomics. 2013 Nov 5;14:758. doi: 10.1186/1471-2164-14-758. 14: 758, Nov 2013.

Wang F, Mullican SE, Dispirito JR, Peed LC, Lazar MA.: Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARγ. Proc Natl Acad Sci U S A. 110(46): 18656-61, Nov 2013.

Schwartz DR, Briggs ER, Qatanani M, Sawaya H, Sebag IA, Picard MH, Scherrer-Crosbie M, Lazar MA.: Human resistin in chemotherapy-induced heart failure in humanized male mice and in women treated for breast cancer. Endocrinology 154(11): 4206-14, Nov 2013.

Gerhart-Hines Z, Feng D, Emmett MJ, Everett LJ, Loro E, Briggs ER, Bugge A, Hou C, Ferrara C, Seale P, Pryma DA, Khurana TS, Lazar MA.: The nuclear receptor Rev-erbα controls circadian thermogenic plasticity. Nature 503(7476): 410-3, Nov 2013.

Ahima RS, Lazar MA.: Physiology. The health risk of obesity--better metrics imperative. Science 341(6148): 856-8, Aug 2013 Notes: doi: 10.1126/science.1241244. No abstract available. [PubMed - in process]

Everett LJ, Lazar MA. : Cell-specific integration of nuclear receptor function at the genome. Wiley Interdiscip Rev Syst Biol Med. Jun 2013 Notes: doi: 10.1002/wsbm.1231. [Epub ahead of print]

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Last updated: 01/29/2014
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