Mitchell A. Lazar, MD, PhD
Mitchell A. Lazar
Sylvan H. Eisman Professor of Medicine
Department: Medicine
Graduate Group Affiliations
Contact information
12-102 Smilow Center for Translational Research
3400 Civic Center Boulevard / 5160
Philadelphia, PA 19104
3400 Civic Center Boulevard / 5160
Philadelphia, PA 19104
Office: (215) 898-0198
Fax: (215) 898-5408
Fax: (215) 898-5408
Email:
lazar@mail.med.upenn.edu
lazar@mail.med.upenn.edu
Publications
Links
Search PubMed for articles
Lazar Lab
Cell and Molecular Biology Graduate Group
Pharmacological Sciences Graduate Group
Institute for Diabetes, Obesity and Metabolism
Search PubMed for articles
Lazar Lab
Cell and Molecular Biology Graduate Group
Pharmacological Sciences Graduate Group
Institute for Diabetes, Obesity and Metabolism
Education:
S.B. (Chemistry)
Massachusetts Institute of Technology, 1976.
Ph.D. (Neuroscience)
Stanford Univerity, 1981.
M.D.
Stanford Univerity, 1982.
Permanent linkS.B. (Chemistry)
Massachusetts Institute of Technology, 1976.
Ph.D. (Neuroscience)
Stanford Univerity, 1981.
M.D.
Stanford Univerity, 1982.
Description of Research Expertise
Research InterestsEpigenomic 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 particuarly interested in 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 histone deacetylase HDAC3. We are studying all aspects of these interactions, using a combination of epigenomic, bioninformatic, and genetic approaches, with particular attention to the nuclear receptors for thyroid hormone as well as the orphan receptor Rev-erbα. Rev-erbα is a key repressive component of the circadian clock that senses heme levels to coordinate metabolism and biological rhythms. 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 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 long sought-after link between obesity and diabetes. We are using ChIP-sequencing and computational biological methods to identify the entire set of genes bound PPARγ in adipocytes and other cell types, and linking this to epigenomic regulation of transcription and metabolism. We also have discovered resistin, a novel hormone and target of PPARg 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 2012-2013
There are numerous potential projects that I would be pleased to discuss in person.
Lab personnel:
Shannon Mullican, Ph.D. (Post-doc)
David Steger, Ph.D. (Research Assistant Professor)
Seo-Hee You, Ph.D. (Post-doc)
Ana Cristancho (M.D./Ph.D. student)
Dan Feng (Graduate Student)
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)
Erika Briggs (Research Specialst)
Lindsey Peed(Research Specialist)
Eric Chen (Research Specialist)
Joe Weaver (Lab Manager)
Selected Publications
Sun Z, Lazar MA.: Dissociating fatty liver and diabetes. Trends Endocrinol Metab Page: [Epub ahead of print] Oct 2012.Yan Q, Carmody RJ, Qu Z, Ruan Q, Jager J, Mullican SE, Lazar MA, Chen YH.: Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome. Proc Natl Acad Sci U S A. Page: [Epub ahead of print] Aug 2012.
Feng D, Lazar MA.: Clocks, metabolism, and the epigenome. Mol Cell. 47(2): 158-67, July 2012.
Lazar MA, Birnbaum MJ.: Physiology. De-meaning of metabolism. Science 336(6089): 1651-2, Jun 2012.
Sinha RA, You SH, Zhou J, Siddique MM, Bay BH, Zhu X, Privalsky ML, Cheng SY, Stevens RD, Summers SA, Newgard CB, Lazar MA, Yen PM.: Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy. J Clin Invest. 122(7): 2428-38, Jun 2012.
Sun Z, Miller RA, Patel RT, Chen J, Dhir R, Wang H, Zhang D, Graham MJ, Unterman TG, Shulman GI, Sztalryd C, Bennett MJ, Ahima RS, Birnbaum MJ, Lazar MA. : Hepatic HDAC3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nature Medicine Page: doi: 10.1038/nm.2744. [Epub ahead of print] May 2012.
Bugge A, Feng D, Everett LJ, Briggs E, Mullican SE, Wang F, Jager J, Lazar MA.: Rev-erbα and β coordinately protect the circadian clock and normal metabolic function. Genes & Development 26(7): 657-67, Apr 2012.
Mullican SE, Gaddis CA, Alenghat T, Nair MG, Giacomin PR, Everett LJ, Feng D, Steger DJ, Schug J, Artis D, Lazar MA.: Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation. Genes Dev. 25(23): 2480-8, Dec 2011.
Baker JF, Morales M, Qatanani M, Cucchiara A, Nackos E, Lazar MA, Teff K, VON Feldt JM.: Resistin Levels in Lupus and Associations with Disease-specific Measures, Insulin Resistance, and Coronary Calcification. J Rheumatol. 38(11): 2369-75, Nov 2011.
Singh N, Trivedi CM, Lu M, Mullican SE, Lazar MA, Epstein JA.: Histone deacetylase 3 regulates smooth muscle differentiation in neural crest cells and development of the cardiac outflow tract. Circ Res. 109(11): 1240-9, Nov 2011.