faculty photo

Mitchell A. Lazar, MD, PhD

Willard and Rhoda Ware Professor in Diabetes and Metabolic Diseases
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
Education:
S.B. (Chemistry)
Massachusetts Institute of Technology, 1976.
Ph.D. (Neuroscience)
Stanford Univerity, 1981.
M.D.
Stanford Univerity, 1982.
Post-Graduate Training
Intern in Internal Medicine, Brigham and Women's Hospital, Boston, MA, 1982-1983.
Resident in Internal Medicine, Brigham and Women's Hospital, Boston, MA, 1983-1985.
Research Fellow in Medicine, Massachusetts General Hospital, Boston, MA, 1985-1985.
Clinical and Research Fellow (Endocrinology), Massachusetts General Hospital, 1985-1986.
Research Associate, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, 1986-1988.
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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 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, bioinformatic, and metabolic phenotyping approaches. We are especially interested in the circadian NR Rev-erb alpha, which utilizes the corepressor complex to potently repress transcription. Rev-erb alpha is a key repressive component of the circadian clock that coordinates metabolism and biological rhythms. We are also studying PPAR gamma, a nuclear receptor that is a master regulator of adipocyte (fat cell) differentiation. Ligands for PPAR gamma have potent antidiabetic activity, and thus PPAR gamma represents a key transcriptional link between obesity and diabetes. The molecular, cellular, and integrative biology of these factors are being studied in mice and humans. We also have discovered resistin, a novel hormone and target of PPAR gamma that is made by fat cells in rodents and by macrophages in humans, and are testing the hypothesis that resistin links metabolism to inflammation in human metabolic diseases.


Rotation Projects for 2017-2018
There are numerous potential projects that I would be pleased to discuss in person.

Lab personnel:
David Steger, Ph.D. (Research Assistant Professor)
Victoria Nelson, Ph.D. (Post-doc)
Dongyin Guan, Ph.D. (Post-doc)
David Hill, M.D., Ph.D. (Post-doc)
Marine Adlanmerini, Ph.D. (Post-doc)
Wenxiang Hu, Ph.D. (Post-doc)
Yehuda Shabtai, Ph.D. (Post-doc)
Pieterjan Dierickx, Ph.D., (Post-doc)
Chunjie Jiang, Ph.D., (Post-doc)
Yong Hoon Kim (Graduate Student)
Hannah Richter (Graduate Student)
Erika Briggs (Research Specialist)
Lindsey Peed (Research Specialist)
Kavya Chgireddy (Bioinformatics Research Specialist)
Wesley Ho (Research Specialist)
Ying Xiong (Research Specialist)
Joe Weaver (Lab Manager)

Selected Publications

Guan D, Xiong Y, Borck PC, Jang C, Doulias PT, Papazyan R, Fang B, Jiang C, Zhang Y, Briggs ER, Hu W, Steger D, Ischiropoulos H, Rabinowitz JD, Lazar MA.: Diet-Induced Circadian Enhancer Remodeling Synchronizes Opposing Hepatic Lipid Metabolic Processes. Cell. 174(4): 831-842.e12, Aug 2018.

Nelson VL, Nguyen HCB, Garcìa-Cañaveras JC, Briggs ER, Ho WY, DiSpirito JR, Marinis JM, Hill DA, Lazar MA.: PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism. Genes Dev. 32(15-16): 1035-1044, Aug 2018.

Zhang Y, Dallner OS, Nakadai T, Fayzikhodjaeva G, Lu YH, Lazar MA, Roeder RG, Friedman JM. : A noncanonical PPARγ/RXRα-binding sequence regulates leptin expression in response to changes in adipose tissue mass. Proc Natl Acad Sci U S A [Epub ahead of print] , Jun 2018 Notes: pii: 201806366. doi: 10.1073/pnas.1806366115.

Lazar MA. : Reversing the curse on PPARγ. J Clin Invest 128(6): 2202-2204, Jun 2018.

Razzoli M, Emmett MJ, Lazar MA, Bartolomucci A. : β-Adrenergic receptors control brown adipose UCP-1 tone and cold response without affecting its circadian rhythmicity. FASEB J. [Epub ahead of print] , May 2018.

Borck PC, Batista TM, Vettorazzi JF, Soares GM, Lubaczeuski C, Guan D, Boschero AC, Vieira E, Lazar MA, Carneiro EM. : Nighttime light exposure enhances Rev-erbα-targeting microRNAs and contributes to hepatic steatosis. Metabolism 85: 250-258, May 2018 Notes: pii: S0026-0495(18)30119-7. doi: 10.1016/j.metabol.2018.05.002.

Hill DA, Lim HW, Kim YH, Ho WY, Foong YH, Nelson VL, Nguyen HCB, Chegireddy K, Kim J, Habertheuer A, Vallabhajosyula P, Kambayashi T, Won KJ, Lazar MA. : Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. Proc Natl Acad Sci U S A. 115(22): E5096-E5105, May 2018.

Kim YH, Marhon SA, Zhang Y, Steger DJ, Won KJ, Lazar MA. : Rev-erbα dynamically modulates chromatin looping to control circadian gene transcription. Science 359(6381): 1274-1277, Mar 2018.

Jang JC, Li J, Gambini L, Batugedara HM, Sati S, Lazar MA, Fan L, Pellecchia M, Nair MG : Human resistin protects against endotoxic shock by blocking LPS-TLR4 interaction. Proc Natl Acad Sci U S A 114(48): E10399-E10408, Nov 2017.

Poleshko A, Shah PP, Gupta M, Babu A, Morley MP, Manderfield LJ, Ifkovits JL, Calderon D, Aghajanian H, Sierra-Pagán JE, Sun Z, Wang Q, Li L, Dubois NC, Morrisey EE, Lazar MA, Smith CL, Epstein JA, Jain R. : Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction. Cell 171(3): 573-587, Oct 2017.

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Last updated: 08/30/2018
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