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 2021-2022
There are numerous potential projects that I would be pleased to discuss in person.

Lab personnel:
Amy Hauck, Ph.D., (Post-doc)
Yang Xiao, Ph.D., (Post-doc)
Kun Zhu, Ph.D., (Post-doc)
Lauren Woodie, Ph.D., (Post-doc)
Michael Tackenberg, Ph.D., (Post-doc)
Shin-Ichi Inoue, Ph.D., (Post-doc)
Tiffany Fleet, M.D., Ph.D., (Post-doc)
Yoon Jeong Park, Ph.D., (Post-doc)
Rashid Mehmood, Ph.D., (Post-doc)
Mohit Midha, Ph.D., (Post-doc)
Delaine Zayas-Bazan Burgos (Graduate Student)
Isaac Celwyn (Research Specialist)
Maria Krieg (Research Specialist)
Lily Melink (Research Specialist)
Yifan Liu (Research Specialist)
Michelle Burrows (Lab Manager)

Selected Publications

Woodie LN, Melink LC, Midha M, de Araújo AM, Geisler CE, Alberto AJ, Krusen BM, Zundell DM, de Lartigue G, Hayes MR, Lazar MA.: Hepatic Vagal Afferents Convey Clock-Dependent Signals to Regulate Circadian Food Intake. bioRxiv[Preprint] Dec 2023 Notes: doi: 10.1101/2023.11.30.568080.

Woodie LN, Melink LC, Alberto AJ, Burrows M, Fortin SM, Chan CC, Hayes MR, Lazar MA.: Hindbrain REV-ERB nuclear receptors regulate sensitivity to diet- induced obesity and brown adipose tissue pathophysiology. Mol Metab. Dec 2023 Notes: doi: 10.1016/j.molmet.2023.101861.

Latimer MN, Williams LJ, Shanmugan G, Carpenter BJ, Lazar MA, Dierickx P, Young ME. : Cardiomyocyte-specific disruption of the circadian BMAL1-REV-ERBα/β regulatory network impacts distinct miRNA species in the murine heart. Commun Biol 6(1): 1149, Nov 2023 Notes: doi: 10.1038/s42003-023-05537-z.

Zhu K, Celwyn IJ, Guan D, Xiao Y, Wang X, Hu W, Jiang C, Cheng L, Casellas R, Lazar MA.: An intrinsically disordered region controlling condensation of a circadian clock component and rhythmic transcription in the liver. Mol Cell. 83(19): 3457-3469.e7, Oct 2023 Notes: doi: 10.1016/j.molcel.2023.09.010.

Lee J, Dimitry JM, Song JH, Son M, Sheehan PW, King MW, Travis Tabor G, Goo YA, Lazar MA, Petrucelli L, Musiek ES.: Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice. Nat Commun 14(1): 5197, Aug 2023 Notes: doi: 10.1038/s41467-023-40927-1.

Mia S, Sonkar R, Williams L, Latimer MN, Rawnsley DR, Rana S, He J, Dierickx P, Kim T, Xie M, Habegger KM, Kubo M, Zhou L, Thomsen MB, Prabhu SD, Frank SJ, Brookes PS, Lazar MA, Diwan A, Young ME. : Novel Roles for the Transcriptional Repressor E4BP4 in Both Cardiac Physiology and Pathophysiology. JACC Basic Transl Sci. doi: 10.1016/j.jacbts.2023.03.016. 8(9): 1141-1156, Jun 2023.

Yamamoto T, Maurya SK, Pruzinsky E, Batmanov K, Xiao Y, Sulon SM, Sakamoto T, Wang Y, Lai L, McDaid KS, Shewale SV, Leone TC, Koves TR, Muoio DM, Dierickx P, Lazar MA, Lewandowski ED, Kelly DP.: RIP140 deficiency enhances cardiac fuel metabolism and protects mice from heart failure. J Clin Invest 133(9): e162309, May 2023.

Guan D, Bae H, Zhou D, Chen Y, Jiang C, La CM, Xiao Y, Zhu K, Hu W, Trinh TM, Liu P, Xiong Y, Cai B, Jang C, Lazar MA.: Hepatocyte SREBP signaling mediates clock communication within the liver. J Clin Invest 133(8): e163018, Apr 2023.

Adlanmerini M, Lazar MA.: The REV-ERB Nuclear Receptors: Timekeepers for the Core Clock Period and Metabolism. Endocrinology 164(6): bqad069, Apr 2023.

Xiao Y, Batmanov K, Hu W, Zhu K, Tom AY, Guan D, Jiang C, Cheng L, McCright SJ, Yang EC, Lanza MR, Liu Y, Hill DA, Lazar MA.: Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis. Sci Transl Med. 15(682): eadc9653, Feb 2023 Notes: doi: 10.1126/scitranslmed.adc9653.

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Last updated: 01/03/2024
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