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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.
Clinical and Research Fellow (Endocrinology), Massachusetts General Hospital, 1985-1986.
Research Fellow in Medicine, Massachusetts General Hospital, Boston, MA, 1985-1985.
Research Associate, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, 1986-1988.
Certifications
American Board of Internal Medicine, 1985.
Endocrinology and Metabolism, 1987.
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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 2016-2017
There are numerous potential projects that I would be pleased to discuss in person.

Lab personnel:
David Steger, Ph.D. (Research Assistant Professor)
Sean Armour, Ph.D. (Post-doc)
Romeo Papazyan, Ph.D. (Post-doc)
Victoria Nelson, Ph.D. (Post-doc)
Paul Titchenell, Ph.D. (Post-doc)
Dongyin Guan, Ph.D. (Post-doc)
David Hill, M.D., Ph.D. (Post-doc)
Zhenghui Li, Ph.D. (Post-doc)
Marine Adlanmerini, Ph.D. (Post-doc)
Wenxiang Hu, Ph.D. (Post-doc)
Matthew Emmett (Graduate Student)
Jarrett Remsberg (Graduate Student)
Yuxiang Zhang (Graduate Student)
Yong Hoon Kim (Graduate Student)
Patricia Borck (Graduate Student)
Erika Briggs (Research Specialist)
Lindsey Peed(Research Specialist)
Manashree Damle (Bioinformatics Research Specialist)
Yee Hoon Foong (Research Specialist)
Wesley Ho (Research Specialist)
Joe Weaver (Lab Manager)

Selected Publications

Papazyan R, Sun Z, Kim YH, Titchenell PM, Hill DA, Lu W, Damle M, Wan M, Zhang Y, Briggs ER, Rabinowitz JD, Lazar MA.: Physiological Suppression of Lipotoxic Liver Damage by Complementary Actions of HDAC3 and SCAP/SREBP. Cell Metab. Nov 2016 Notes: pii: S1550-4131(16)30543-5. doi: 10.1016/j.cmet.2016.10.012. [Epub ahead of print]

Bass J, Lazar MA.: Circadian time signatures of fitness and disease. Science 354(6315): 994-999, Nov 2016.

Teng X, Emmett MJ, Lazar MA, Goldberg E, Rabinowitz JD.: Lactate Dehydrogenase C Produces S-2-Hydroxyglutarate in Mouse Testis. ACS Chem Biol. 11(9): 2420-7, Sep 2016.

Ferrannini G, Namwanje M, Fang B, Damle D, Li D, Liu Q, Lazar MA, Qiang L. : Genetic background determine brown remodeling of white fat in rodents. Molecular Metabolism 5(10): 948-958, Aug 2016.

Zhang Y, Fang B, Damle M, Guan D, Li Z, Kim YH, Gannon M, Lazar MA.: HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms. Genes Dev. 30(14): 1636-44, July 2016 Notes: doi: 10.1101/gad.281972.116.

Zhang L, He X, Liu L, Jiang M, Zhao C, Wang H, He D, Zheng T, Zhou X, Hassan A, Ma Z, Xin M, Sun Z, Lazar MA, Goldman SA, Olson EN, Richard Lu Q.: Hdac3 Interaction with p300 Histone Acetyltransferase Regulates the Oligodendrocyte and Astrocyte Lineage Fate Switch. Dev Cell. 37(6): doi: 10.1016/j.devcel.2016.06.004. June 2016.

Jager J, Wang F, Fang B, Lim HW, Peed LC, Steger DJ, Won KJ, Kharitonenkov A, Adams AC, Lazar MA.: The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-Specific Fibroblast Growth Factor 21 (FGF21) Signaling. J Biol Chem. 291(20): 10867-75, May 2016 Notes: pii: jbc.M116.719120. [Epub ahead of print]

Wang Y, Frank DB, Morley MP, Zhou S, Wang X, Lu MM, Lazar MA, Morrisey EE.: HDAC3-Dependent Epigenetic Pathway Controls Lung Alveolar Epithelial Cell Remodeling and Spreading via miR-17-92 and TGF-β Signaling Regulation. Dev Cell 36(3): 303-15, Feb 2016.

Zhang L, He X, Liu L, Jiang M, Zhao C, Wang H, He D, Zheng T, Zhou X, Hassan A, Ma Z, Xin M, Sun Z, Lazar MA, Goldman SA, Olson EN, Lu QR.: Hdac3 Interaction with p300 Histone Acetyltransferase Regulates the Oligodendrocyte and Astrocyte Lineage Fate Switch. Dev Cell 36(3): 316-30, Feb 2016.

Hong S, Zhou W, Fang B, Lu W, Loro E, Damle M, Ding, Jager J, Zhang S, Zhang Y, Feng D, Chu Q, Dill BD, Khurana TS, Rabinowitz JD, Lazar MA (co-corresponding), Sun Z. : Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3. Nature Medicine In Press, 2016.

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Last updated: 11/29/2016
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