Mitchell
A. Lazar, M.D., Ph.D.
Sylvan H. Eisman Professor of Medicine & Genetics
Chief, Division of Endocrinology, Diabetes & Metabolism
Director, Institute for Diabetes, Obesity and Metabolism
Program
Summary
Receptor for
small lipophilic hormones, such as thyroid hormone and retinoic
acid, regulate gene expression by binding to and altering
the transcription of target genes. We are studying the mechanisms
by which the receptors regulate gene transcription. In the
absence of ligand, TRs interact with corepressor molecules
to repress transcription. Thyroid hormone binding alters
TR conformation and destabilizes the corepressor complex,
while leading to recruitment of coactivator complexes. These
complexes contain histone modifying activities that may
be drug targets. We are dissecting the molecular and cellular
biology of these transcription complexes. Understanding
the mechanisms underlying tissue- and target gene-specificity
of hormone action will allow improved patient care and facilitate
the development of new rational therapies for a variety
of diseases, including myeloid leukemias whose pathogenesis
has been linked to corepressor biology.
Diabetes is a major cause of morbidity and mortality in
the U.S. More than 95% of diabetics have type 2 diabetes,
associated with obesity and severe resistance to the action
of insulin. We are studying the molecular mechanisms of
nuclear receptors called PPARs, which actively promote adipogenesis.
Excitement has been generated by the observation that PPAR
ligands include prostaglandins as well as a promising new
class of antidiabetic drugs called thiazolidinediones (TZDs),
including troglitazone (RezulinR), pioglitazone (ActosR),
and rosiglitazone (AvandiaR). These drugs enhance the actions
of insulin. The mechanism whereby PPAR activation leads
to increased insulin sensitivity is not known. We have identified
and are currently characterizing novel target genes that
may subserve these functions.
Publications Please visit PubMed
for a complete list of publications.
Reilly MP, Lehrke M, Wolfe ML, Rohatgi A, Lazar MA, Rader DJ. Resistin Is an Inflammatory Marker of Atherosclerosis in Humans. Circulation. 2005 Feb 14; [Epub ahead of print] PMID: 15710760 [PubMed - as supplied by publisher]
Ishizuka T, Lazar MA. The Nuclear Receptor Corepressor Deacetylase Activating Domain is Essential for Repression by Thyroid Hormone Receptor. Mol Endocrinol. 2005 Feb 3; [Epub ahead of print] PMID: 15695367 [PubMed - as supplied by publisher]
Steppan CM, Wang J, Whiteman EL, Birnbaum MJ, Lazar MA. Activation of SOCS-3 by resistin. Mol Cell Biol. 2005 Feb;25(4):1569-75. PMID: 15684405 [PubMed - in process]
Guan HP, Ishizuka T, Chui PC, Lehrke M, Lazar MA. Corepressors selectively control the transcriptional activity of PPAR{gamma} in adipocytes. Genes Dev. 2005 Feb 15;19(4):453-61. Epub 2005 Jan 28. PMID: 15681609 [PubMed - in process]
Lazar MA. How obesity causes diabetes: not a tall tale. Science. 2005 Jan 21;307(5708):373-5. PMID: 15662001 [PubMed - indexed for MEDLINE]
