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Mitchell A. Lazar, MD, PhD
Mitchell A. Lazar, MD, PhD
Sylvan Eisman Professor of Medicine
Chief, Division of Endocrinology, Diabetes, and Metabolism
Director, Institute for Diabetes, Obesity, and Metabolism
Perelman School of Medicine at the University of Pennsylvania
12-102 Smilow Center for Translational Research
3400 Civic Center Blvd., Bldg. 421
Philadelphia, PA 19104
The Lazar Lab is interested in the transcriptional regulation of metabolism by nuclear receptors, particularly in the context of obesity, insulin resistance and diabetes. Lazar Lab members are studying how nuclear receptor signaling and adipocytokines contribute to cardiovascular disease, which is the leading cause of death in diabetes.
The Lazar laboratory is studying the transcriptional and epigenomic regulation of metabolism with a keen focus upon 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. The Lazar Lab investigates all aspects of these interactions, using a combination of epigenomic, bioinformatic, 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 knock-in and knock-out models.
The Lab is also studying PPARγ, a nuclear receptor that is a master regulator of adipocyte (fat cell) differentiation using ChIP-sequencing and computational biological methods to identify the entire set of genes bound to PPARγ in adipocytes and other cell types, and linking this to epigenomic regulation of transcription and metabolism. Ligands for PPARγ have potent antidiabetic activity, and thus PPARγ represents a long sought-after link between obesity and diabetes.
The Lab discovered resistin, a novel hormone and target of PPARγ made and secreted by fat cells in rodents and by macrophages in humans, has demonstrated that resistin regulates insulin responsiveness, and is now using mice humanized for resistin to test the hypothesis that resistin links metabolism to inflammation in human metabolic diseases.
The Lazar Lab is comprised of post-doctoral researchers, research specialists and graduate students.
- Shannon Mullican, PhD
- David Steger, PhD
Research Assistant Professor
- Seo-Hee You, PhD
- Ana Cristancho MD
- Dan Feng
- Fenfen Wang
- Sonia Step
- Ray Soccio, MD, PhD
- Zheng Sun, PhD
- Joanna DiSpirito, PhD
- Logan Everett, PhD
- Jennifer Jager, PhD
- Zachary Gerhart-Hines, PhD
- Bin Fang, PhD
- Jill Marinis, PhD
- Sean Armour, PhD
- Erika Briggs
- Lindsey Peed
- Eric Chen
- Jessa Tunacao
- Joe Weaver
- 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. Nat Med. 2012;18:934–942. PMID: 22561686
- Bugge A, Feng D, Everett LJ, Briggs ER, Mullican SE, Wang F, Jager J, Lazar MA. Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function. Genes Dev. 2012;26:657-667. PMID:22474260
- 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. 2011;25:2480-2488. PMID: 22156208
- 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. 2011;109:1240-1249. PMID: 21959220
- Cristancho AG, Lazar MA. Forming functional fat: a growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol. 2011;12:722-734. PMID: 21952300
- Cristancho AG, Schupp M, Lefterova MI, Cao S, Cohen DM, Chen CS, Steger DJ, Lazar MA. Repressor transcription factor 7-like 1 promotes adipogenic competency in precursor cells. Proc Natl Acad Sci USA. 2011;108:16271-16276. PMC3182685
- Sun Z, Feng D, Everett LJ, Bugge A, Lazar MA. Circadian Epigenomic Remodeling and Hepatic Lipogenesis: Lessons from HDAC3. Cold Spring Harb Symp Quant Biol. 2011;76:49-55. PMID: 21900149
- Sun Z, Singh N, Mullican SE, Everett LJ, Li L, Yuan L, Liu X, Epstein JA, Lazar MA. Diet-induced lethality due to loss of HDAC3 in heart and skeletal muscle. J Biol Chem. 2011. 23;286:33301-33309. PMID: 21808063
- Prokesch A, Lazar MA. A hormone sends instant messages to the genome. Cell. 2011;145:499-501. PMID: 21565609