Faculty

Mitchell A. Lazar, MD, PhD

faculty photo
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.
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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

Hu W, Jiang C, Kim M, Yang W, Zhu K, Guan D, Lv W, Xiao Y, Wilson JR, Rader DJ, Pui CH, Relling MV, Lazar MA.: Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids. Cell Metab. 33(8): 1592-1609, Aug 2021.

Guan D, Lazar MA.: Interconnections between circadian clocks and metabolism. J Clin Invest 131(15): e148278, Aug 2021.

Xiao Y, Kim M, Lazar MA.: Nuclear receptors and transcriptional regulation in non-alcoholic fatty liver disease. Mol Metab 50: 101119, Aug 2021 Notes: doi: 10.1016/j.molmet.2020.101119.

Gillen AE, Fu R, Riemondy KA, Jager J, Fang B, Lazar MA, Martin SL.: Liver Transcriptome Dynamics During Hibernation Are Shaped by a Shifting Balance Between Transcription and RNA Stability. Front Physiol 12: 662132, May 2021 Notes: doi: 10.3389/fphys.2021.662132. eCollection 2021.

Shabtai Y, Nagaraj NK, Batmanov K, Cho YW, Guan Y, Jiang C, Remsberg J, Forrest D, Lazar MA.: A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver. Genes Dev 35(5-6): 367-378, Mar 2021 Notes: doi: 10.1101/gad.345686.120.

Adlanmerini M, Nguyen HC, Krusen BM, Teng CW, Geisler CE, Peed LC, Carpenter BJ, Hayes MR, Lazar MA.: Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice. J Clin Invest 131(1): e140424, Jan 2021 Notes: doi: 10.1172/JCI140424.

Fang B, Guan D, Lazar MA.: Using GRO-Seq to Measure Circadian Transcription and Discover Circadian Enhancers. Methods Mol Biol 2130: 127-148, 2021 Notes: doi: 10.1007/978-1-0716-0381-9_10.

Kim YH, Lazar MA.: Transcriptional Control of Circadian Rhythms and Metabolism: A Matter of Time and Space. Endocr Rev. 41(5): bnaa014, Oct 2020.

Guan D, Xiong Y, Trinh TM, Xiao Y, Hu W, Jiang C, Dierickx P, Jang C, Rabinowitz JD, Lazar MA.: The hepatocyte clock and feeding control chronophysiology of multiple liver cell types. Science. 369(6509): 1388-1394, Sept 2020 Notes: doi: 10.1126/science.aba8984. Online ahead of print.

Nguyen HCB, Adlanmerini M, Hauck AK, Lazar MA.: Dichotomous engagement of HDAC3 activity governs inflammatory responses. Nature 584(7820): 286-290, Aug 2020 Notes: doi: 10.1038/s41586-020-2576-2. Online ahead of print.

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Last updated: 09/15/2021
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