About

Mitchell A. Lazar, MD, PhD, is the Willard and Rhoda Ware Professor in Diabetes and Metabolic Diseases at the Perelman School of Medicine at the University of Pennsylvania. He serves as the Director of the Penn Diabetes Research Center, Founding Director of the Institute for Diabetes, Obesity and Metabolism, and Director of the Cox Institute for Medical Research. His research focuses on the transcriptional regulation of metabolism, particularly the role played by nuclear receptors (NRs). Lazar's laboratory studies how nuclear receptors bind to DNA and function as transcriptional repressors in the absence of ligands, recruiting corepressor complexes that include histone deacetylase 3 (HDAC3). His work investigates the tissue-specific and physiological roles of these corepressor complexes using genomic, genetic, proteomic, bioinformatic, and metabolic phenotyping approaches. Lazar is especially interested in the circadian nuclear receptor Rev-erb alpha, which represses transcription to coordinate metabolism and biological rhythms, and PPAR gamma, a master regulator of adipocyte differentiation with potent antidiabetic activity. His research also explores resistin, a hormone linked to metabolism and inflammation in human metabolic diseases. Lazar's contributions include elucidating mechanisms underlying obesity-associated insulin resistance and diabetes, and understanding the epigenomic regulation of transcription and metabolism by nuclear receptors.

Research topics

• Biochemistry
• Cell biology
• Biology
• Endocrinology
• Chemistry

Selected publications

• Author Correction: Circadian circuits control plasticity of group 3 innate lymphoid cells by sustaining epigenetic configuration of RORγt

  Nature Immunology · 2026-03-27

  articleOpen access
  PublisherOA PDFDOI

• Reduction in Hepatic Phosphatidylcholine Biosynthesis Promotes MASH Through Copper Deficiency

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-14

  articleOpen access

  Abstract Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease for which the mechanisms linking lipid dysregulation to fibrosis remain poorly defined. Hepatic phosphatidylcholine (PC) content is reduced in MASH, but how this alteration drives disease progression is unclear. Here, we identify a role for copper (Cu) homeostasis as a downstream effector of impaired PC biosynthesis. Using single-nucleus RNA sequencing in complementary genetic and dietary mouse models, we found that reduced hepatic PC is associated with marked depletion of hepatic Cu and a concomitant increase in circulating Cu, indicating disrupted Cu distribution. Mechanistically, PC depletion impaired plasma membrane localization of the high-affinity Cu transporter CTR1 ( SLC31A1 ) in hepatocytes, limiting Cu uptake. In human hepatic stellate cells, Cu promoted fibrogenic activation, whereas suppression of Cu import or pharmacologic inhibition of MAPK signaling attenuated fibronectin deposition. In vivo , liver-directed Cu supplementation restored hepatic Cu levels and reduced steatosis but failed to improve fibrosis. In contrast, pharmacologic Cu chelation with bathocuproinedisulfonic acid (BCS) reduced fibrosis without affecting inflammation. Together, these findings identify Cu redistribution as a consequence of impaired PC biosynthesis and implicate Cu-dependent signaling in stellate cell activation, fibrogenesis and MASH pathogenesis. Graphical Abstract

  PublisherDOI

• Author Correction: Nutrient-sensing nuclear receptors coordinate autophagy

  Nature · 2026-01-27

  articleOpen access
  PublisherOA PDFDOI

• REV-ERB-alpha and -beta coordinately regulate astrocyte reactivity and proteostatic function

  Proceedings of the National Academy of Sciences · 2026-01-30

  articleOpen access

  The molecular circadian clock is a ubiquitous transcriptional–translational feedback loop that regulates CNS function, glial responses, and neurodegenerative pathology. The nuclear receptors REV-ERB-α ( Nr1d1 ) and REV-ERB-β ( Nr1d2 ) are components of the core circadian clock which regulate metabolism, neuroinflammatory responses, synaptic pruning, and protein aggregation, though the cell type–specific effects and relative compensatory effects of REV-ERB-α AND -β in the brain are unknown. To study the CNS functions of REV-ERBs, we developed mouse lines with global or astrocyte-specific, conditional knockout of both REV-ERB-α and -β. We demonstrate that inducible postnatal global deletion of both REV-ERB-α and -β unmasks extensive transcriptional changes in the brain in disease-relevant pathways such as protein catabolism, complement, and oxidative stress which are not observed with REV-ERB-α deletion alone, and drives spontaneous astrocyte reactivity. Astrocyte-specific deletion of REV-ERB-α/-β recapitulates this spontaneous astrocyte reactivity phenotype, indicating that REV-ERBs regulate astrocyte activation in a cell-autonomous manner downstream of the core circadian clock. Upstream transcription factor analysis revealed that REV-ERB-α/-β repress transcription of Stat3 , and astrocytic deletion of REV-ERBs induced astrocytic STAT3 expression and downstream STAT3-mediated gene expression, providing a mechanistic link to the astrocyte reactivity shift. Dual REV-ERB deletion enhanced astrocyte alpha-synuclein uptake and protein degradation in vitro and mitigated alpha-synuclein spreading pathology in an in vivo model of Parkinson’s Disease. This study reveals REV-ERBs as regulators of astrocyte function and implicates astrocyte REV-ERBs as potential therapeutic targets to prevent synucleinopathies and other neurodegenerative pathologies.

  PublisherOA PDFDOI

• CD9 regulates macrophage-mediated remodeling of adipose tissue in obesity

  JCI Insight · 2026-02-10

  articleOpen access

  Dysfunctional white adipose tissue contributes to the development of obesity-related morbidities, including insulin resistance, dyslipidemia, and other metabolic disorders. Adipose tissue macrophages (ATMs) accumulate in obesity and play both beneficial and harmful roles in the maintenance of adipose tissue homeostasis and function. Despite their importance, the molecules and mechanisms that regulate these diverse functions are not well understood. Lipid-associated macrophages (LAMs), the dominant subset of obesity-associated ATMs, accumulate in crown-like structures and are characterized by a metabolically activated and proinflammatory phenotype. We previously identified CD9 as a surface marker of LAMs. However, the contribution of CD9 to the activation and function of LAMs during obesity is unknown. Using a myeloid-specific CD9-KO model, we show that CD9 supports ATM-adipocyte adhesion and crown-like structure formation. Furthermore, CD9 promotes the expression of profibrotic and extracellular matrix remodeling genes. Loss of myeloid CD9 reduces adipose tissue fibrosis, increases visceral adipose tissue accumulation, and improves global metabolic outcomes during diet-induced obesity. These results identify CD9 as a causal regulator of pathogenic LAM functions, highlighting CD9 as a potential therapeutic target for treating obesity-associated metabolic disease.

  PublisherDOI

• A non-apoptotic caspase-8–meteorin pathway in hepatocytes promotes MASH fibrosis

  Nature Metabolism · 2025-09-26 · 3 citations

  articleOpen access

  Metabolic-dysfunction-associated steatohepatitis (MASH) is the leading cause of chronic liver disease, but an incomplete understanding of MASH-induced liver fibrosis has limited therapeutic options. Here we show that hepatocyte caspase-8 drives MASH fibrosis through an apoptosis-independent mechanism. Hepatic caspase-8 expression correlates with liver fibrosis in both human and experimental MASH, and hepatocyte-specific caspase-8 deletion in male mice with MASH suppressed liver fibrosis and hepatic stellate cell (HSC) activation without affecting hepatocyte apoptosis. Mechanistic studies showed that a caspase-8-YY1 pathway in hepatocytes induces secretory meteorin (Metrn), which activates HSCs via a c-Kit-STAT3 pathway. Meteorin expression was increased in human and male mouse MASH livers and decreased by deletion of hepatocyte caspase-8 in MASH mice and human and mouse primary hepatocytes. Genetic restoration of hepatocyte meteorin in hepatocyte-caspase-8-deleted MASH mice restored HSC activation and liver fibrosis while silencing hepatocyte meteorin lowered liver fibrosis. These findings reveal a therapeutically targetable pathway promoting MASH fibrosis involving a non-apoptotic function of caspase-8 and a newly discovered HSC activator, meteorin.

  PublisherOA PDFDOI

• The time is now: accounting for time-of-day effects to improve reproducibility and translation of metabolism research

  Nature Metabolism · 2025-03-17 · 18 citations

  reviewOpen access
  PublisherOA PDFDOI

• REV-ERBα regulates brain NAD+ levels and tauopathy via an NFIL3–CD38 axis

  Nature Aging · 2025-09-01 · 6 citations

  articleOpen access

  Nicotinamide adenine dinucleotide (NAD+) is a critical metabolic co-enzyme implicated in brain aging, and augmenting NAD+ levels in the aging brain is an attractive therapeutic strategy for neurodegeneration. However, the molecular mechanisms of brain NAD+ regulation are incompletely understood. In cardiac tissue, the circadian nuclear receptor REV-ERBα has been shown to regulate NAD+ via control of the NAD+-producing enzyme NAMPT. Here we show that REV-ERBα controls brain NAD+ levels through a distinct pathway involving NFIL3-dependent suppression of the NAD+-consuming enzyme CD38, particularly in astrocytes. REV-ERBα deletion does not affect NAMPT expression in the brain and has an opposite effect on NAD+ levels as in the heart. Astrocytic REV-ERBα deletion augments brain NAD+ and prevents tauopathy in P301S mice. Our data reveal that REV-ERBα regulates NAD+ in a tissue-specific manner via opposing regulation of NAMPT versus CD38 and define an astrocyte REV-ERBα–NFIL3–CD38 pathway controlling brain NAD+ metabolism and neurodegeneration. Lee et al. show that the circadian clock protein REV-ERBα controls brain NAD+ levels by regulating the NAD+-consuming enzyme CD38. Global or astrocytic REV-ERBα deletion or pharmacologic REV-ERB inhibition protects against tau pathology in mice.

  PublisherOA PDFDOI

• Circadian circuits control plasticity of group 3 innate lymphoid cells by sustaining epigenetic configuration of RORγt

  Nature Immunology · 2025-08-13 · 11 citations

  article
  PublisherDOI

• Normal circadian period length requires repression of Npas2 by REV-ERB nuclear receptors

  Cell Reports · 2025-10-01 · 3 citations

  articleOpen accessSenior author

  REV-ERB nuclear receptors are integrated into the molecular circadian clock present in most mammalian cells. Loss of REV-ERBs (REV-ERB DKO) within the suprachiasmatic nucleus (SCN) in vivo leads to a marked shortening of the circadian period, but it remains unclear whether REV-ERB regulation of circadian period is tissue autonomous, if it is conserved across tissues, and how it is established. Here, we show that period shortening in the absence of REV-ERBs is tissue autonomous, is consistent between brain and liver, and is brought about through derepression of clock transcription factors NPAS2 and CLOCK. Thus, in addition to disruption of synchrony with the external environment, our results demonstrate that the circadian impacts of REV-ERB loss also include the alteration of core circadian properties with tissue-specific consequences.

  PublisherDOI

Recent grants

• University of Pennsylvania Diabetes Research Center

  NIH · $17.0M · 1997–2027

• Integrative Physiology of Thyroid Hormone Receptors and Nuclear Receptor Corepressors

  NIH · $6.6M · 1991–2029

• Nuclear Receptors in Metabolic Tissues

  NIH · $12.1M · 1995–2026

• Biology of REV-ERB nuclear receptors

  NIH · $12.8M · 1992–2025

• NIH Grant U19DK062434

  NIH · $51.6M · 2012

Frequent coauthors

• Ángel R. de Lera

  137 shared

• Pierre Chambon

  Institut de génétique et de biologie moléculaire et cellulaire

  132 shared

• Pierre Germain

  Courant Institute of Mathematical Sciences

  132 shared

• Hinrich Gronemeyer

  Centre National de la Recherche Scientifique

  129 shared

• David J. Mangelsdorf

  The University of Texas Southwestern Medical Center

  129 shared

• Ronald M. Evans

  Salk Institute for Biological Studies

  129 shared

• Reuben Lotan

  128 shared

• Gregor Eichele

  Max Planck Institute for Multidisciplinary Sciences

  128 shared

Labs

• Lazar LabPI

Education

• MA (Honorary)

  University of Pennsylvania

• MD

  Stanford University School of Medicine

  1982

• PhD (Neuroscience)

  Stanford University School of Medicine

  1981

• S.B. (Chemistry)

  Massachusetts Institute of Technology

  1976