Mitch Lazar
Sylvan H. Eisman Professor, and Director of the Institute for Diabetes, Obesity, and Metabolism

Genetics and Gene Regulation Program

Address

700 Clinical Research Building
415 Curie Boulevard
Philadelphia, Pennsylvania 19104-6145

Office tel.: 215 898-0198
Lab tel.: 215 898-0199
Fax: 215 573-9999
E-mail: lazar@mail.med.upenn.edu

Link(s)

Lazar Lab

Institute for Diabetes, Obesity, and Metabolism

Education

Massachusetts Institute of Technology, S.B. (Chemistry),1976

Stanford University School of Medicine, Ph.D.
(Neuroscience), 1981

Stanford University School of Medicine, M.D., 1982

Research Interests

• Regulation of gene expression and metabolism by nuclear hormone receptors
• Mechanism of obesity-associated insulin resistance and diabetes

Key words: nuclear receptors, transcription, metabolism, diabetes, endocrinology

Description of Research

The Lazar laboratory is interested in mechanisms by which nuclear receptors (NRs) regulate gene expression and metabolism. NRs are transcription factors that are activated by binding to small lipophilic ligands including hormones, vitamins, drugs, and metabolites. In the absence of ligand, NRs bind to DNA and function as potent transcriptional repressors. Repression is mediated by corepressor complexes that include chromatin modulating histone deacetylases (HDACs). Ligand binding alters the conformation of the receptor, causing corepressor to dissociate, coactivator proteins to be recruited, and gene transcription to be turned on. We are studying all aspects of these interactions, with special interest in corepressor complexes containing HDAC3, and with particular attention to the nuclear receptors for thyroid hormone and anti-diabetic drugs, as well as the orphan receptor Rev-erba. Rev-erba 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 cell lines as well as mouse gene knockin and knockout models.

We are also studying PPARγ (peroxisome proliferator activated receptor), 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 have discovered new PPARγ target genes and identified a novel pathway of corepressor control of these genes, and are now using genome-wide chromatin immunoprecipitation to better understand the genetic mechanisms underlying PPARγ regulation of adipocyte lipid metabolism. We also have discovered resistin, a novel hormone made and secreted by fat cells in rodents and by macrophages in humans. We have demonstrated that resistin regulates insulin responsiveness, and are now studying the molecular physiology of resistin in mouse and human models.

Selected Publications

Yin L, Wu N, Curtin JC, Qatanani M, Szwergold NR, Reid RA, Waitt GM, Pearce KH, Wisely GB, Lazar MA. Rev-erba is a heme sensor that coordinates metabolic and circadian pathways. Science 318:1789-1789, 2007

Yin L, Wang J, Klein PS, Lazar MA. Nuclear receptor Rev-erba is a critical lithium-sensitive component of the circadian clock. Science 311:102-105, 2006.

Hartman HB, Yu J, Alenghat T, Ishizuka T, Lazar MA. The histone binding code of nuclear receptor corepressors matches the substrate specificity of histone deacetylase 3. EMBO Reports, 6:445-451, 2005.

Guan H-P, Ishizuka T, Chui PC, Lehrke M, Lazar MA. Corepressors selectively control the transcriptional activity of PPARγ in adipocytes. Genes & Development, 19:453-461, 2005.

Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhodes B, Qi Y, Wang J, Rajala MW, Pocai A, Scherer PE, Steppan CM, Ahima RS, Obici S, Rossetti L, Lazar MA. Regulation of fasted blood glucose by resistin. Science 303:1195-1198, 2004.

Search PubMed for more articles

Lab

Rotation Projects

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

Lab personnel:

Ana Cristancho (M.D./Ph.D. student)
Dan Feng (Graduate student)
Elyisha Hanniman (Post-doc)
Martina Lefterova (MD./PhD student)
Shannon Mullican, Ph.D. (Post-doc)
Mo Qatanani, Ph.D. (Post-doc)
Caroline Phelan (Graduate Student)
Michael Schupp, Ph.D. (Post-doc)
Ray Soccio, M.D., Ph.D. (Post-doc)
David Steger, Ph.D. (Research Associate)
Takuya Tomaru, M.D., Ph.D. (Post-doc)
Nan Wu (Graduate student)
Lei Yin, Ph.D. (Research Associate)
Seo-Hee You, Ph.D. (Post-doc)