@article{pmid15695367,

title = {The nuclear receptor corepressor deacetylase activating domain is essential for repression by thyroid hormone receptor},

author = {Takahiro Ishizuka and Mitchell A Lazar},

doi = {10.1210/me.2005-0009},

issn = {0888-8809},

year  = {2005},

date = {2005-06-01},

journal = {Mol Endocrinol},

volume = {19},

number = {6},

pages = {1443--1451},

abstract = {Nuclear receptor corepressor (N-CoR) mediates repression by thyroid hormone receptor (TR) as well as other nuclear hormone receptors and transcription factors. N-CoR contains several repression domains that repress transcription when fused to a heterologous DNA binding domain, but their relative importance in the full-length N-CoR molecule is unknown. Here we addressed this important issue by depleting N-CoR in human cells and replacing it with mutant and wild-type murine N-CoR. Although the N-terminal RD binds transducin beta-like protein 1 (TBL1), TBLR1, and mSin3, deletion of this region did not affect the ability of N-CoR to mediate repression by TR. By contrast, deletion of the deacetylase activating domain (DAD) that binds and activates histone deacetylase 3 dramatically hampered N-CoR's function as a TR corepressor. Introduction of a single amino acid mutation in the DAD similarly disabled the corepressor function of N-CoR. Thus, the DAD domain of N-CoR is singularly essential for repression by TR.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15741250,

title = {Resistin levels in human immunodeficiency virus-infected patients with lipoatrophy decrease in response to rosiglitazone},

author = {Daniel Kamin and Colleen Hadigan and Michael Lehrke and Sasha Mazza and Mitchell A Lazar and Steven Grinspoon},

doi = {10.1210/jc.2005-0287},

issn = {0021-972X},

year  = {2005},

date = {2005-06-01},

journal = {J Clin Endocrinol Metab},

volume = {90},

number = {6},

pages = {3423--3426},

abstract = {Resistin is a recently recognized adipocytokine thought to contribute to insulin resistance. We determined resistin levels and metabolic parameters in 24 HIV-infected men and women with lipoatrophy and hyperinsulinemia and studied the effect of 12 wk of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone (4-8 mg/d) on resistin in these subjects. Participants completed metabolic testing before and after rosiglitazone including fasting determination of resistin, adiponectin, and leptin levels, serum inflammatory markers, and hyperinsulinemic euglycemic clamp testing. Resistin concentration decreased significantly after rosiglitazone (12.17 +/- 1.15 ng/ml to 10.23 +/- 1.05 ng/ml; P = 0.02), in conjunction with significant increases in adiponectin- (P < 0.001) and insulin- stimulated glucose disposal (P = 0.004). Leptin levels, as well as TNF-alpha, did not change with rosiglitazone. In summary, among HIV-infected subjects with insulin resistance and lipoatrophy, resistin levels decreased significantly after rosiglitazone. Further investigation into the physiological role of this peroxisome proliferator-activated receptor-gamma-responsive adipocytokine in the metabolic abnormalities associated with HIV is warranted.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15761026,

title = {The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene},

author = {Lei Yin and Mitchell A Lazar},

doi = {10.1210/me.2005-0057},

issn = {0888-8809},

year  = {2005},

date = {2005-06-01},

journal = {Mol Endocrinol},

volume = {19},

number = {6},

pages = {1452--1459},

abstract = {Transcriptional regulation plays a fundamental role in controlling circadian oscillation of clock gene expression. The orphan nuclear receptor Rev-erbalpha has recently been implicated as a major regulator of the circadian clock. Expression of Bmal1, the master regulator of circadian rhythm in mammals, is negatively correlated with Rev-erbalpha mRNA level, but the molecular mechanism underlying this regulation is largely unknown. Here we show that Rev-erbalpha dramatically represses the basal activity of the mouse Bmal1 gene promoter via two monomeric binding sites, both of which are required for repression and are conserved between mouse and human. Rev-erbalpha directly binds to the mouse Bmal1 promoter and recruits the endogenous nuclear receptor corepressor (N-CoR)/histone deacetylase 3 (HDAC3) complex, in association with a decrease in histone acetylation. The endogenous N-CoR/HDAC3 complex is also associated with the endogenous Bmal1 promoter in human HepG2 liver cells, where a reduction in cellular HDAC3 level markedly increases the expression of Bmal1 mRNA. These data demonstrate a new function for the N-CoR/HDAC3 complex in regulating the expression of genes involved in circadian rhythm by functioning as corepressor for Rev-erbalpha.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15811852,

title = {Coactivators and corepressors of NF-kappaB in IkappaB alpha gene promoter},

author = {Zhanguo Gao and Paul Chiao and Xia Zhang and Xiaohong Zhang and Mitchell A Lazar and Edward Seto and Howard A Young and Jianping Ye},

doi = {10.1074/jbc.M500754200},

issn = {0021-9258},

year  = {2005},

date = {2005-06-01},

journal = {J Biol Chem},

volume = {280},

number = {22},

pages = {21091--21098},

abstract = {In this study, we investigated recruitment of coactivators (SRC-1, SRC-2, and SRC-3) and corepressors (HDAC1, HDAC2, HDAC3, SMRT, and NCoR) to the IkappaB alpha gene promoter after NF-kappaB activation by tumor necrosis factor-alpha. Our data from chromatin immunoprecipitation assay suggest that coactivators and corepressors are simultaneously recruited to the promoter, and their binding to the promoter DNA is oscillated in HEK293 cells. SRC-1, SRC-2, and SRC-3 all enhanced IkappaB alpha transcription. However, the interaction of each coactivator with the promoter exhibited different patterns. After tumor necrosis factor-alpha treatment, SRC-1 signal was increased gradually, but SRC-2 signal was reduced immediately, suggesting replacement of SRC-2 by SRC-1. SRC-3 signal was increased at 30 min, reduced at 60 min, and then increased again at 120 min, suggesting an oscillation of SRC-3. The corepressors were recruited to the promoter together with the coactivators. The binding pattern suggests that the corepressor proteins formed two types of corepressor complexes, SMRT-HDAC1 and NCoR-HDAC3. The two complexes exhibited a switch at 30 and 60 min. The functions of cofactors were confirmed by gene overexpression and RNA interference-mediated gene knockdown. These data suggest that gene transactivation by the transcription factor NF-kappaB is subject to the regulation of a dynamic balance between the coactivators and corepressors. This model may represent a mechanism for integration of extracellular signals into a precise control of gene transcription.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15832170,

title = {The histone-binding code of nuclear receptor co-repressors matches the substrate specificity of histone deacetylase 3},

author = {Helen B Hartman and Jiujiu Yu and Theresa Alenghat and Takahiro Ishizuka and Mitchell A Lazar},

doi = {10.1038/sj.embor.7400391},

issn = {1469-221X},

year  = {2005},

date = {2005-05-01},

journal = {EMBO Rep},

volume = {6},

number = {5},

pages = {445--451},

abstract = {Ligands for nuclear receptors facilitate the exchange of co-repressors for coactivators, leading to chromatin modifications that favour the activation of gene transcription. Here, we show that the repressed state of an endogenous retinoic acid-regulated gene is quickly re-established after ligand removal. As expected, repression is characterized by recruitment of N-CoR/SMRT-HDAC3 (histone deacetylase 3) co-repressor complexes, leading to local histone hypoacetylation. The achievement of the repressed state involves the ordered deacetylation of lysines in H4 tails. This order is determined by the inherent substrate specificity of HDAC3, and unexpectedly predicts the binding preference of N-CoR/SMRT for submaximally acetylated H4 tails. The match between the specificity of acetyl-histone deacetylation by HDAC3 and the histone-binding preference of N-CoR/SMRT allows the co-repressor complex to stabilize and propagate repression of nuclear hormone receptor gene targets.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16054077,

title = {Diet-dependent cardiovascular lipid metabolism controlled by hepatic LXRalpha},

author = {Michael Lehrke and Corinna Lebherz and Segan C Millington and Hong-Ping Guan and John Millar and Daniel J Rader and James M Wilson and Mitchell A Lazar},

doi = {10.1016/j.cmet.2005.04.005},

issn = {1550-4131},

year  = {2005},

date = {2005-05-01},

journal = {Cell Metab},

volume = {1},

number = {5},

pages = {297--308},

abstract = {The high-cholesterol/high-fat Western diet has abetted an epidemic of atherosclerotic cardiovascular disease, the leading cause of death in industrialized nations. Liver X receptors (LXRs) are oxysterol sensors that are required for normal cholesterol and triglyceride homeostasis, yet synthetic LXR agonists produce undesirable hypertriglyceridemia. Here we report a previously unrecognized role for hepatic LXRalpha in the links between diet, serum lipids, and atherosclerosis. A modest increase in hepatic LXRalpha worsened serum lipid profiles in LDL-receptor null mice fed normal chow but had the opposite effect on lipids and afforded strong protection against atherosclerosis on a Western diet. The beneficial effect of hepatic LXRalpha was abrogated by a synthetic LXR agonist, which activated SREBP-1c and its target genes. Thus, the interplay between diet and hepatic LXRalpha is a critical determinant of serum lipid profiles and cardiovascular risk, and selective modulation of LXR target genes in liver can ameliorate hyperlipidemia and cardiovascular disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15837933,

title = {Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors},

author = {Anna Codina and James D Love and Yun Li and Mitchell A Lazar and David Neuhaus and John W R Schwabe},

doi = {10.1073/pnas.0500299102},

issn = {0027-8424},

year  = {2005},

date = {2005-04-01},

journal = {Proc Natl Acad Sci U S A},

volume = {102},

number = {17},

pages = {6009--6014},

abstract = {SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) and NCoR (nuclear receptor corepressor) are transcriptional corepressors that play an essential role in the regulation of development and metabolism. This role is achieved, in part, through the recruitment of a key histone deacetylase (HDAC3), which is itself indispensable for cell viability. The assembly of HDAC3 with the deacetylase activation domain (DAD) of SMRT and NCoR is required for activation of the otherwise inert deacetylase. The DAD comprises an N-terminal DAD-specific motif and a C-terminal SANT (SWI3/ADA2/NCoR/TFIIIB)-like domain. We report here the solution structure of the DAD from SMRT, which reveals a four-helical structure. The DAD differs from the SANT (and MYB) domains in that (i) it has an additional N-terminal helix and (ii) there is a notable hydrophobic groove on the surface of the domain. Structure-guided mutagenesis, combined with interaction assays, showed that residues in the vicinity of the hydrophobic groove are required for interaction with (and hence activation of) HDAC3. Importantly, one surface-exposed lysine is required for activation of HDAC3, but not for interaction. This lysine may play a uniquely important role in the mechanism of activating HDAC3.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15681609,

title = {Corepressors selectively control the transcriptional activity of PPARgamma in adipocytes},

author = {Hong-Ping Guan and Takahiro Ishizuka and Patricia C Chui and Michael Lehrke and Mitchell A Lazar},

doi = {10.1101/gad.1263305},

issn = {0890-9369},

year  = {2005},

date = {2005-02-01},

journal = {Genes Dev},

volume = {19},

number = {4},

pages = {453--461},

abstract = {Peroxisome proliferator-activated receptor gamma (PPARgamma) is the master regulator of adipogenesis as well as the target of thiazolidinedione (TZD) antidiabetic drugs. Many PPARgamma target genes are induced during adipogenesis, but others, such as glycerol kinase (GyK), are expressed at low levels in adipocytes and dramatically up-regulated by TZDs. Here, we have explored the mechanism whereby an exogenous PPARgamma ligand is selectively required for adipocyte gene expression. The GyK gene contains a functional PPARgamma-response element to which endogenous PPARgamma is recruited in adipocytes. However, unlike the classic PPARgamma-target gene aP2, which is constitutively associated with coactivators, the GyK gene is targeted by nuclear receptor corepressors in adipocytes. TZDs trigger the dismissal of corepressor histone deacetylase (HDAC) complexes and the recruitment of coactivators to the GyK gene. TZDs also induce PPARgamma-Coactivator 1alpha (PGC-1alpha), whose recruitment to the GyK gene is sufficient to release the corepressors. Thus, selective modulation of adipocyte PPARgamma target genes by TZDs involves the dissociation of corepressors by direct and indirect mechanisms.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15684405,

title = {Activation of SOCS-3 by resistin},

author = {Claire M Steppan and Juan Wang and Eileen L Whiteman and Morris J Birnbaum and Mitchell A Lazar},

doi = {10.1128/MCB.25.4.1569-1575.2005},

issn = {0270-7306},

year  = {2005},

date = {2005-02-01},

journal = {Mol Cell Biol},

volume = {25},

number = {4},

pages = {1569--1575},

abstract = {Resistin is an adipocyte hormone that modulates glucose homeostasis. Here we show that in 3T3-L1 adipocytes, resistin attenuates multiple effects of insulin, including insulin receptor (IR) phosphorylation, IR substrate 1 (IRS-1) phosphorylation, phosphatidylinositol-3-kinase (PI3K) activation, phosphatidylinositol triphosphate production, and activation of protein kinase B/Akt. Remarkably, resistin treatment markedly induces the gene expression of suppressor of cytokine signaling 3 (SOCS-3), a known inhibitor of insulin signaling. The 50% effective dose for resistin induction of SOCS-3 is approximately 20 ng/ml, close to levels of resistin in serum. Association of SOCS-3 protein with the IR is also increased by resistin. Inhibition of SOCS function prevented resistin from antagonizing insulin action in adipocytes. SOCS-3 induction is the first cellular effect of resistin that is independent of insulin and is a likely mediator of resistin's inhibitory effect on insulin signaling in adipocytes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15710760,

title = {Resistin is an inflammatory marker of atherosclerosis in humans},

author = {Muredach P Reilly and Michael Lehrke and Megan L Wolfe and Anand Rohatgi and Mitchell A Lazar and Daniel J Rader},

doi = {10.1161/01.CIR.0000155620.10387.43},

issn = {1524-4539},

year  = {2005},

date = {2005-02-01},

journal = {Circulation},

volume = {111},

number = {7},

pages = {932--939},

abstract = {BACKGROUND: Resistin, a plasma protein, induces insulin resistance in rodents. Recent reports suggest that circulating levels of resistin are elevated in obese and insulin-resistant rodents and humans. Whereas rodent resistin is made in adipocytes, macrophages are a major source of human resistin. Given the convergence of adipocyte and macrophage function, resistin may provide unique insight into links between obesity, inflammation, and atherosclerosis in humans.nnMETHODS AND RESULTS: We examined whether plasma resistin levels were associated with metabolic and inflammatory markers, as well as with coronary artery calcification (CAC), a quantitative index of atherosclerosis, in 879 asymptomatic subjects in the Study of Inherited Risk of Coronary Atherosclerosis. Resistin levels were positively associated with levels of inflammatory markers, including soluble tumor necrosis factor-alpha receptor-2 (P<0.001), interleukin-6 (P=0.04), and lipoprotein-associated phospholipase A2 (P=0.002), but not measures of insulin resistance in multivariable analysis. Resistin levels also were associated (odds ratio and 95% confidence interval in ordinal regression) with increasing CAC after adjustment for age, sex, and established risk factors (OR, 1.23 [CI, 1.03 to 1.52], P=0.03) and further control for metabolic syndrome and plasma C-reactive protein (CRP) levels (OR, 1.25 [CI, 1.04 to 1.50], P=0.01). In subjects with metabolic syndrome, resistin levels further predicted CAC, whereas CRP levels did not.nnCONCLUSIONS: Plasma resistin levels are correlated with markers of inflammation and are predictive of coronary atherosclerosis in humans, independent of CRP. Resistin may represent a novel link between metabolic signals, inflammation, and atherosclerosis. Further studies are needed to define the relationship of resistin to clinical cardiovascular disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15662001,

title = {How obesity causes diabetes: not a tall tale},

author = {Mitchell A Lazar},

doi = {10.1126/science.1104342},

issn = {1095-9203},

year  = {2005},

date = {2005-01-01},

journal = {Science},

volume = {307},

number = {5708},

pages = {373--375},

abstract = {The epidemic of obesity-associated diabetes is a major crisis in modern societies, in which food is plentiful and exercise is optional. The biological basis of this problem has been explored from evolutionary and mechanistic perspectives. Evolutionary theories, focusing on the potential survival advantages of "thrifty" genes that are now maladaptive, are of great interest but are inherently speculative and difficult to prove. Mechanistic studies have revealed numerous fat-derived molecules and a link to inflammation that, together, are hypothesized to underlie the obesity-diabetes connection and thereby represent prospective targets for therapeutic intervention.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15733730,

title = {PPAR gamma, 10 years later},

author = {Mitchell A Lazar},

doi = {10.1016/j.biochi.2004.10.021},

issn = {0300-9084},

year  = {2005},

date = {2005-01-01},

journal = {Biochimie},

volume = {87},

number = {1},

pages = {9--13},

abstract = {It is now over 10 years since the discovery of peroxisome proliferator activated receptor gamma (PPAR gamma) and its unique role in adipogenesis. The subsequent identification of PPAR gamma as the target of insulin sensitizing drugs certified this ligand-regulated transcription factor as an exciting link between adipocyte biology and peripheral insulin resistance. Here, I summarize the great progress that has been made over the past decade in elucidating the biology of PPAR gamma and its role in adipogenesis and glucose metabolism. Prospects for future research leading to new therapies for obesity and diabetes are also discussed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15520860,

title = {Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone},

author = {Leanne Wilson-Fritch and Sarah Nicoloro and My Chouinard and Mitchell A Lazar and Patricia C Chui and John Leszyk and Juerg Straubhaar and Michael P Czech and Silvia Corvera},

doi = {10.1172/JCI21752},

issn = {0021-9738},

year  = {2004},

date = {2004-11-01},

journal = {J Clin Invest},

volume = {114},

number = {9},

pages = {1281--1289},

abstract = {Adipose tissue plays a central role in the control of energy homeostasis through the storage and turnover of triglycerides and through the secretion of factors that affect satiety and fuel utilization. Agents that enhance insulin sensitivity, such as rosiglitazone, appear to exert their therapeutic effect through adipose tissue, but the precise mechanisms of their actions are unclear. Rosiglitazone changes the morphological features and protein profiles of mitochondria in 3T3-L1 adipocytes. To examine the relevance of these effects in vivo, we studied white adipocytes from ob/ob mice during the development of obesity and after treatment with rosiglitazone. The levels of approximately 50% of gene transcripts encoding mitochondrial proteins were decreased with the onset of obesity. About half of those genes were upregulated after treatment with rosiglitazone, and this was accompanied by an increase in mitochondrial mass and changes in mitochondrial structure. Functionally, adipocytes from rosiglitazone-treated mice displayed markedly enhanced oxygen consumption and significantly increased palmitate oxidation. These data reveal mitochondrial remodeling and increased energy expenditure in white fat in response to rosiglitazone treatment in vivo and suggest that enhanced lipid utilization in this tissue may affect whole-body energy homeostasis and insulin sensitivity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15578112,

title = {An inflammatory cascade leading to hyperresistinemia in humans},

author = {Michael Lehrke and Muredach P Reilly and Segan C Millington and Nayyar Iqbal and Daniel J Rader and Mitchell A Lazar},

doi = {10.1371/journal.pmed.0010045},

issn = {1549-1676},

year  = {2004},

date = {2004-11-01},

journal = {PLoS Med},

volume = {1},

number = {2},

pages = {e45},

abstract = {BACKGROUND: Obesity, the most common cause of insulin resistance, is increasingly recognized as a low-grade inflammatory state. Adipocyte-derived resistin is a circulating protein implicated in insulin resistance in rodents, but the role of human resistin is uncertain because it is produced largely by macrophages.nnMETHODS AND FINDINGS: The effect of endotoxin and cytokines on resistin gene and protein expression was studied in human primary blood monocytes differentiated into macrophages and in healthy human participants. Inflammatory endotoxin induced resistin in primary human macrophages via a cascade involving the secretion of inflammatory cytokines that circulate at increased levels in individuals with obesity. Induction of resistin was attenuated by drugs with dual insulin-sensitizing and anti-inflammatory properties that converge on NF-kappaB. In human study participants, experimental endotoxemia, which produces an insulin-resistant state, causes a dramatic rise in circulating resistin levels. Moreover, in patients with type 2 diabetes, serum resistin levels are correlated with levels of soluble tumor necrosis factor alpha receptor, an inflammatory marker linked to obesity, insulin resistance, and atherosclerosis.nnCONCLUSIONS: Inflammation is a hyperresistinemic state in humans, and cytokine induction of resistin may contribute to insulin resistance in endotoxemia, obesity, and other inflammatory states.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15340149,

title = {RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract},

author = {David Artis and Mei Lun Wang and Sue A Keilbaugh and Weimian He and Mario Brenes and Gary P Swain and Pamela A Knight and Deborah D Donaldson and Mitchell A Lazar and Hugh R P Miller and Gerhard A Schad and Phillip Scott and Gary D Wu},

doi = {10.1073/pnas.0404034101},

issn = {0027-8424},

year  = {2004},

date = {2004-09-01},

journal = {Proc Natl Acad Sci U S A},

volume = {101},

number = {37},

pages = {13596--13600},

abstract = {Gastrointestinal (GI) nematode infections are an important public health and economic concern. Experimental studies have shown that resistance to infection requires CD4(+) T helper type 2 (Th2) cytokine responses characterized by the production of IL-4 and IL-13. However, despite >30 years of research, it is unclear how the immune system mediates the expulsion of worms from the GI tract. Here, we demonstrate that a recently described intestinal goblet cell-specific protein, RELMbeta/FIZZ2, is induced after exposure to three phylogenetically distinct GI nematode pathogens. Maximal expression of RELMbeta was coincident with the production of Th2 cytokines and host protective immunity, whereas production of the Th1 cytokine, IFN-gamma, inhibited RELMbeta expression and led to chronic infection. Furthermore, whereas induction of RELMbeta was equivalent in nematode-infected wild-type and IL-4-deficient mice, IL-4 receptor-deficient mice showed minimal RELMbeta induction and developed persistent infections, demonstrating a direct role for IL-13 in optimal expression of RELMbeta. Finally, we show that RELMbeta binds to components of the nematode chemosensory apparatus and inhibits chemotaxic function of a parasitic nematode in vitro. Together, these results suggest that intestinal goblet cell-derived RELMbeta may be a novel Th2 cytokine-induced immune-effector molecule in resistance to GI nematode infection.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15189975,

title = {Abnormal glucose homeostasis due to chronic hyperresistinemia},

author = {Shamina M Rangwala and A Sophie Rich and Ben Rhoades and Jennifer S Shapiro and Silvana Obici and Luciano Rossetti and Mitchell A Lazar},

doi = {10.2337/diabetes.53.8.1937},

issn = {0012-1797},

year  = {2004},

date = {2004-08-01},

journal = {Diabetes},

volume = {53},

number = {8},

pages = {1937--1941},

abstract = {Resistin is an adipocyte-secreted protein that circulates at increased levels in obesity. Acute administration of resistin impairs glucose tolerance, but the effects of chronic hyperresistinemia have not been established. Here we describe the generation and characterization of transgenic mice that have high circulating levels of resistin in the setting of normal weight. Fasted blood glucose was higher in resistin-transgenic mice than in their nontransgenic littermates, and glucose tolerance was impaired in the hyperresistinemic mice. Metabolic studies in the setting of a hyperinsulinemic-euglycemic clamp protocol revealed that chronically hyperresistinemic mice have elevated glucose production. This increase in glucose production may be partly explained by increased expression of hepatic phosphoenolpyruvate carboxykinase. Thus, chronic hyperresistinemia impairs normal glucose metabolism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15165749,

title = {Peroxisome proliferator-activated receptor gamma in diabetes and metabolism},

author = {Shamina M Rangwala and Mitchell A Lazar},

doi = {10.1016/j.tips.2004.03.012},

issn = {0165-6147},

year  = {2004},

date = {2004-06-01},

journal = {Trends Pharmacol Sci},

volume = {25},

number = {6},

pages = {331--336},

abstract = {The peroxisome proliferator-activated receptor gamma (PPAR-gamma) has been the focus of intense research during the past decade because ligands for this receptor have emerged as potent insulin sensitizers used in the treatment of type 2 diabetes. Recent advances include the discovery of novel genes that are regulated by PPAR-gamma, which helps explain how activation of this adipocyte-predominant transcription factor regulates glucose and lipid homeostasis. Increased levels of circulating free fatty acids and lipid accumulation in non-adipose tissue have been implicated in the development of insulin resistance. This situation is improved by PPAR-gamma ligands, which promote fatty acid storage in fat depots and regulate the expression of adipocyte-secreted hormones that impact on glucose homeostasis. The net result of the pleiotropic effects of PPAR-gamma ligands is improvement of insulin sensitivity, although undesired side-effects limit the utility of this therapy. It might be possible to dissociate the anti-diabetic and adverse effects through selective modulation of PPAR-gamma activity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15156183,

title = {ETO interacting proteins},

author = {Bruce A Hug and Mitchell A Lazar},

doi = {10.1038/sj.onc.1207674},

issn = {0950-9232},

year  = {2004},

date = {2004-05-01},

journal = {Oncogene},

volume = {23},

number = {24},

pages = {4270--4274},

abstract = {The 8;21 translocation produces a fusion between the ETO gene and that encoding the myeloid transcription factor AML1. The AML1-ETO fusion substitutes the majority of the ETO protein for the coregulator recruitment domains of AML1. Biochemical analyses of ETO have led to the identification of numerous interacting proteins including many corepressors. Importantly, the proteins interacting with ETO are different from those of wild-type AML1, suggesting that altered coregulator recruitment underlies the oncogenic properties of AML1-ETO. The list of corepressors capable of binding ETO includes histone deacetylases (HDACs) and components of distinct HDAC core complexes. These investigations have provided mechanistic insight into corepressor recruitment by ETO and clues to the leukemogenic activity of AML1-ETO.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid15049878,

title = {The current biology of resistin},

author = {Claire M Steppan and Mitchell A Lazar},

doi = {10.1111/j.1365-2796.2004.01306.x},

issn = {0954-6820},

year  = {2004},

date = {2004-04-01},

journal = {J Intern Med},

volume = {255},

number = {4},

pages = {439--447},

abstract = {Obesity and noninsulin-dependent diabetes mellitus are globally epidemic. Insulin resistance is a major contributor to the pathogenesis of type II diabetes and plays a role in numerous other metabolic disorders including hypertension, dyslipidaemia and atherosclerosis. Obesity, in particular visceral adiposity, is positively correlated with insulin resistance. Although this correlation between adiposity and insulin resistance is well established in human beings as well as in rodent models, the mechanisms involved in obesity-related insulin resistance are not fully defined. One mechanism is that factors secreted from adipocytes can affect peripheral insulin resistance. One candidate for such a factor is resistin, an adipocyte-secreted hormone that impairs glucose homeostasis and insulin action in the mouse. This review will summarize our current understanding of resistin and will attempt to provide a framework for future study of its role in rodent and human physiology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid14645235,

title = {The coiled-coil domain is the structural determinant for mammalian homologues of Drosophila Sina-mediated degradation of promyelocytic leukemia protein and other tripartite motif proteins by the proteasome},

author = {Mirco Fanelli and Anna Fantozzi and Pasquale De Luca and Sara Caprodossi and Shu-ichi Matsuzawa and Mitchell A Lazar and Pier Giuseppe Pelicci and Saverio Minucci},

doi = {10.1074/jbc.M306407200},

issn = {0021-9258},

year  = {2004},

date = {2004-02-01},

journal = {J Biol Chem},

volume = {279},

number = {7},

pages = {5374--5379},

abstract = {Mammalian homologues of Drosophila Seven in Absentia (SIAHs) target for proteasome-mediated degradation several factors involved in cell growth and tumorigenesis. Here we show that SIAH-1/2 binds and targets for proteasome-mediated degradation the putative tumor suppressor and tripartite motif (TRIM) family member PML, leading to the loss of its transcriptional co-activating properties and a reduction in the number of endogenous PML nuclear bodies. Association with PML requires the substrate-binding domain (SBD) of SIAH-1/2 through an interacting surface apparently distinct from those predicted by the structural studies, or shown experimentally to mediate binding to SIAH-associated factors. Within PML, the coiled-coil domain is required for Siah- and proteasome-mediated degradation, and deletions of regions critical for the integrity of this region impair the ability of Siah to trigger PML-RAR degradation. Fusion of the coiled-coil domain to heterologous proteins resulted in the capacity of mSiah-2 to target their degradation. All of the TRIM proteins tested were degraded upon mSiah-2 overexpression. Finally, we show that the fusion protein PML-RAR (that retains the coiled-coil domain), which causes acute promyelocytic leukemias, is also a potential substrate of mSiah-2. As a result of mSiah-2 overexpression and subsequent degradation of the fusion protein, the arrest in hematopoietic differentiation because of expression of PML-RAR is partially rescued. These results identify PML and other TRIMs as new factors post-translationally regulated by SIAH and involve the coiled-coil region of PML and of other SIAH substrates as a novel structural determinant for targeted degradation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid14976316,

title = {Regulation of fasted blood glucose by resistin},

author = {Ronadip R Banerjee and Shamina M Rangwala and Jennifer S Shapiro and A Sophie Rich and Ben Rhoades and Yong Qi and Juan Wang and Michael W Rajala and Alessandro Pocai and Phillipp E Scherer and Claire M Steppan and Rexford S Ahima and Silvana Obici and Luciano Rossetti and Mitchell A Lazar},

doi = {10.1126/science.1092341},

issn = {1095-9203},

year  = {2004},

date = {2004-02-01},

journal = {Science},

volume = {303},

number = {5661},

pages = {1195--1198},

abstract = {The association between obesity and diabetes supports an endocrine role for the adipocyte in maintaining glucose homeostasis. Here we report that mice lacking the adipocyte hormone resistin exhibit low blood glucose levels after fasting, due to reduced hepatic glucose production. This is partly mediated by activation of adenosine monophosphate-activated protein kinase and decreased expression of gluconeogenic enzymes in the liver. The data thus support a physiological function for resistin in the maintenance of blood glucose during fasting. Remarkably, lack of resistin diminishes the increase in post-fast blood glucose normally associated with increased weight, suggesting a role for resistin in mediating hyperglycemia associated with obesity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid14561740,

title = {A chromatin immunoprecipitation screen reveals protein kinase Cbeta as a direct RUNX1 target gene},

author = {Bruce A Hug and Nazia Ahmed and Jonathan A Robbins and Mitchell A Lazar},

doi = {10.1074/jbc.M309524200},

issn = {0021-9258},

year  = {2004},

date = {2004-01-01},

journal = {J Biol Chem},

volume = {279},

number = {2},

pages = {825--830},

abstract = {RUNX1 (also known as AML1) is a DNA-binding transcription factor that functions as a tumor suppressor and developmental determinant in hematopoietic cells. Target promoters have been identified primarily through the use of differential expression strategies and candidate gene approaches but not biochemical screens. Using a chromatin immunoprecipitation screen, we identified protein kinase Cbeta as a direct RUNX1 target gene and demonstrate that endogenous RUNX1 binds the chromatinized protein kinase Cbeta promoter of U937 cells. A phylogenetically conserved RUNX1-binding site within the PKCbeta promoter binds RUNX1 in electrophoretic mobility shift analyses and confers RUNX1 responsiveness on a heterologous promoter. Changes in RUNX1 activity affect endogenous protein kinase Cbeta expression, and a dominant-negative form of RUNX1 protects U937 cells from apoptotic stimuli previously shown to be dependent on protein kinase Cbeta. This protection can be reversed by the ectopic expression of protein kinase Cbeta. Together these findings demonstrate that protein kinase Cbeta is a direct, downstream target of RUNX1 and links RUNX1 to a myeloid apoptotic pathway.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid14702104,

title = {East meets West: an herbal tea finds a receptor},

author = {Mitchell A Lazar},

doi = {10.1172/JCI20661},

issn = {0021-9738},

year  = {2004},

date = {2004-01-01},

journal = {J Clin Invest},

volume = {113},

number = {1},

pages = {23--25},

abstract = {Jaundice, which is caused by accumulation of bilirubin, is extremely common in newborn infants. Phototherapy is an effective treatment, but a drug therapy would also be desirable. A Chinese herbal remedy for jaundice called Yin Zhi Huang is now shown to activate a liver receptor that enhances the clearance of bilirubin (see the related article beginning on page 137). This discovery could lead to improved pharmaceutical treatments for neonatal jaundice.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid14598255,

title = {Bacterial colonization leads to the colonic secretion of RELMbeta/FIZZ2, a novel goblet cell-specific protein},

author = {Weimian He and Mei-Lun Wang and Han-Qing Jiang and Claire M Steppan and Marcus E Shin and M Christine Thurnheer and John J Cebra and Mitchell A Lazar and Gary D Wu},

doi = {10.1016/j.gastro.2003.07.009},

issn = {0016-5085},

year  = {2003},

date = {2003-11-01},

journal = {Gastroenterology},

volume = {125},

number = {5},

pages = {1388--1397},

abstract = {BACKGROUND & AIMS: Goblet cells are highly polarized exocrine cells found throughout the small and large intestine that have a characteristic morphology due to the accumulation of apical secretory granules. These granules contain proteins that play important physiologic roles in cellular protection, barrier function, and proliferation. A limited number of intestinal goblet cell-specific proteins have been identified. In this study, we investigate the expression and regulation of RELMbeta, a novel colon-specific gene.nnMETHODS: The regulation of RELMbeta messenger RNA expression was determined in LS174T, Caco-2, and HT-29 cell lines in response to stimulation with interleukin 13 and lipopolysaccharide. Quantitative reverse-transcription polymerase chain reaction, immunoblots, and immunohistochemistry were used to examine the expression of RELMbeta in BALB/c and C.B17.SCID mice housed in conventional, germ-free, and gnotobiotic environments.nnRESULTS: Messenger RNA for RELMbeta is restricted to the undifferentiated, proliferating colonic epithelium. Immunohistochemistry shows that this protein is expressed in goblet cells located primarily in the distal half of the colon and cecum with lower levels detectable in the proximal colon. High levels of RELMbeta can be detected in the stool of mice and humans, where it exists as a homodimer under nonreducing conditions. Interestingly, the secretion of RELMbeta is dramatically reduced in germ-free mice. Furthermore, introduction of germ-free mice into a conventional environment results in enhanced expression and robust secretion of RELMbeta within 48 hours.nnCONCLUSIONS: These studies define a new goblet cell-specific protein and provide the first evidence that colon-specific gene expression can be regulated by colonization with normal enteric bacteria.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid14536066,

title = {Genetic modulation of PPARgamma phosphorylation regulates insulin sensitivity},

author = {Shamina M Rangwala and Ben Rhoades and Jennifer S Shapiro and A Sophie Rich and Jason K Kim and Gerald I Shulman and Klaus H Kaestner and Mitchell A Lazar},

doi = {10.1016/s1534-5807(03)00274-0},

issn = {1534-5807},

year  = {2003},

date = {2003-10-01},

journal = {Dev Cell},

volume = {5},

number = {4},

pages = {657--663},

abstract = {Obesity-associated diabetes is epidemic in industrialized societies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in adipose tissue and the presumed molecular target for antidiabetic thiazolidinedione drugs that reverse insulin resistance but also promote weight gain. Phosphorylation reduces the activity of PPARgamma in vitro, but physiological relevance has not been demonstrated. We have studied mice homozygous for a mutation (S112A) that prevents PPARgamma phosphorylation. Surprisingly, the weights and adipose mass of PPARgamma-S112A mice are not greater than wild-type. Remarkably, however, genetic prevention of PPARgamma phosphorylation preserves insulin sensitivity in the setting of diet-induced obesity. Underlying this protection are smaller fat cells, elevated serum adiponectin, and reduced free fatty acid levels. Thus, the phosphorylation state of PPARgamma modulates insulin sensitivity. Compounds that prevent PPARgamma phosphorylation or ligands that induce the conformation of nonphosphorylated PPARgamma may selectively enhance insulin sensitivity without increasing body weight.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid12861000,

title = {The N-CoR/histone deacetylase 3 complex is required for repression by thyroid hormone receptor},

author = {Takahiro Ishizuka and Mitchell A Lazar},

doi = {10.1128/MCB.23.15.5122-5131.2003},

issn = {0270-7306},

year  = {2003},

date = {2003-08-01},

journal = {Mol Cell Biol},

volume = {23},

number = {15},

pages = {5122--5131},

abstract = {Nuclear receptor corepressors (N-CoR) and silencing mediator for retinoid and thyroid receptors (SMRT) have both been implicated in thyroid hormone receptor (TR)-mediated repression. Here we show that endogenous N-CoR, TBL1, and histone deacetylase 3 (HDAC3), but not HDAC1, -2, or -4, are recruited to a stably integrated reporter gene repressed by unliganded TR as well as the orphan receptor RevErb. Unliganded TR also recruits this complex to a transiently transfected reporter, and transcriptional repression is associated with local histone deacetylation that is reversed by the presence of thyroid hormone. Knockdown of N-CoR using small interfering RNAs markedly reduces repression by the TR ligand binding domain in human 293T cells, whereas knockdown of SMRT has little effect. RevErb repression appears to involve both corepressors in this system. Knockdown of HDAC3 markedly reduces repression by both TR and RevErb, while knockdown of HDAC1 or 2 has more modest, partly nonspecific effects. Thus, HDAC3 is critical for repression by multiple nuclear receptors and the N-CoR HDAC3 complex plays a unique and necessary role in TR-mediated gene repression in human 293T cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid12925689,

title = {Thyroid hormone action: a binding contract},

author = {Mitchell A Lazar},

doi = {10.1172/JCI19479},

issn = {0021-9738},

year  = {2003},

date = {2003-08-01},

journal = {J Clin Invest},

volume = {112},

number = {4},

pages = {497--499},

abstract = {Thyroid hormones are critical for differentiation, growth, and metabolism. A new study investigating the biological role of the TH receptor TR-beta has demonstrated that DNA binding is critical for most of its functions, but also suggests that novel mechanisms independent of DNA binding may contribute to regulation of auditory function by TR-beta.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid12840002,

title = {A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylation},

author = {Jiujiu Yu and Yun Li and Takahiro Ishizuka and Matthew G Guenther and Mitchell A Lazar},

doi = {10.1093/emboj/cdg326},

issn = {0261-4189},

year  = {2003},

date = {2003-07-01},

journal = {EMBO J},

volume = {22},

number = {13},

pages = {3403--3410},

abstract = {Nuclear receptor corepressors SMRT (silencing mediator of retinoid and thyroid receptors) and N-CoR (nuclear receptor corepressor) recruit histone deacetylase (HDAC) activity to targeted regions of chromatin. These corepressors contain a closely spaced pair of SANT motifs whose sequence and organization is highly conserved. The N-terminal SANT is a critical component of a deacetylase activation domain (DAD) that binds and activates HDAC3. Here, we show that the second SANT motif functions as part of a histone interaction domain (HID). The HID enhances repression by increasing the affinity of the DAD-HDAC3 enzyme for histone substrate. The two SANT motifs synergistically promote histone deacetylation and repression through unique functions. The HID contribution to repression is magnified by its ability to inhibit histone acetyltransferase enzyme activity. Remarkably, the SANT-containing HID preferentially binds to unacetylated histone tails. This implies that the SMRT HID participates in interpreting the histone code in a feed-forward mechanism that promotes and maintains histone deacetylation at genomic sites of SMRT recruitment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid12700889,

title = {Resistin: molecular history and prognosis},

author = {Ronadip R Banerjee and Mitchell A Lazar},

doi = {10.1007/s00109-003-0428-9},

issn = {0946-2716},

year  = {2003},

date = {2003-04-01},

journal = {J Mol Med (Berl)},

volume = {81},

number = {4},

pages = {218--226},

abstract = {Obesity and diabetes have reached epidemic proportions worldwide. The antidiabetic thiazolidinedione (TZD) drugs are insulin-sensitizing agents now widely used in the treatment of type 2 diabetes. TZDs are ligands for the nuclear hormone receptor peroxisome proliferator activated receptor gamma, which is a master regulator of adipogenesis and adipocyte metabolism. The molecular mechanisms by which TZDs improve insulin sensitivity have not been fully identified. Here we consider a novel secreted factor first identified as a TZD-suppressible gene in mouse adipocytes, called resistin, and discuss what is currently known about resistin regulation and function in mouse and human.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid12668657,

title = {Histone deacetylase 4 interacts with 53BP1 to mediate the DNA damage response},

author = {Gary D Kao and W Gillies McKenna and Matthew G Guenther and Ruth J Muschel and Mitchell A Lazar and Tim J Yen},

doi = {10.1083/jcb.200209065},

issn = {0021-9525},

year  = {2003},

date = {2003-03-01},

journal = {J Cell Biol},

volume = {160},

number = {7},

pages = {1017--1027},

abstract = {Anumber of proteins are recruited to nuclear foci upon exposure to double-strand DNA damage, including 53BP1 and Rad51, but the precise role of these DNA damage-induced foci remain unclear. Here we show in a variety of human cell lines that histone deacetylase (HDAC) 4 is recruited to foci with kinetics similar to, and colocalizes with, 53BP1 after exposure to agents causing double-stranded DNA breaks. HDAC4 foci gradually disappeared in repair-proficient cells but persisted in repair-deficient cell lines or cells irradiated with a lethal dose, suggesting that resolution of HDAC4 foci is linked to repair. Silencing of HDAC4 via RNA interference surprisingly also decreased levels of 53BP1 protein, abrogated the DNA damage-induced G2 delay, and radiosensitized HeLa cells. Our combined results suggest that HDAC4 is a critical component of the DNA damage response pathway that acts through 53BP1 and perhaps contributes in maintaining the G2 cell cycle checkpoint.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid14631849,

title = {Biochemical isolation and analysis of a nuclear receptor corepressor complex},

author = {Matthew G Guenther and Mitchell A Lazar},

doi = {10.1016/s0076-6879(03)64014-0},

issn = {0076-6879},

year  = {2003},

date = {2003-01-01},

journal = {Methods Enzymol},

volume = {364},

pages = {246--257},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16604174,

title = {Nuclear receptor corepressors},

author = {Mitchell A Lazar},

doi = {10.1621/nrs.01001},

issn = {1550-7629},

year  = {2003},

date = {2003-01-01},

journal = {Nucl Recept Signal},

volume = {1},

pages = {e001},

abstract = {The ability of NR LBDs to transfer repression function to a heterologous DNA binding domain, and the cross-squelching of repression by untethered LBDs, has suggested that repression is mediated by interactions with putative cellular corepressor proteins. The yeast-two hybrid screen for protein interactors has proven to be the key to the isolation and characterization of corepressors. This short review will focus on N-CoR and SMRT.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid12502735,

title = {Assembly of the SMRT-histone deacetylase 3 repression complex requires the TCP-1 ring complex},

author = {Matthew G Guenther and Jiujiu Yu and Gary D Kao and Tim J Yen and Mitchell A Lazar},

doi = {10.1101/gad.1037502},

issn = {0890-9369},

year  = {2002},

date = {2002-12-01},

journal = {Genes Dev},

volume = {16},

number = {24},

pages = {3130--3135},

abstract = {The acetylation of histone tails is a primary determinant of gene activity. Histone deacetylase 3 (HDAC3) requires the nuclear receptor corepressor SMRT for HDAC enzyme activity. Here we report that HDAC3 interacts with SMRT only after priming by cellular chaperones including the TCP-1 ring complex (TRiC), which is required for proper folding of HDAC3 in an ATP-dependent process. SMRT displaces TRiC from HDAC3, yielding an active HDAC enzyme. The SMRT-HDAC3 repression complex thus joins the VHL-elongin BC tumor suppression complex and the cyclin E-Cdk2 cell cycle regulation complex as critical cellular machines requiring TRiC for proper assembly and function. The strict control of HDAC3 activity underscores the cellular imperative that histone deacetylation occur only in targeted regions of the genome.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid12357248,

title = {A futile metabolic cycle activated in adipocytes by antidiabetic agents},

author = {Hong-Ping Guan and Yong Li and Mette Valentin Jensen and Christopher B Newgard and Claire M Steppan and Mitchell A Lazar},

doi = {10.1038/nm780},

issn = {1078-8956},

year  = {2002},

date = {2002-10-01},

journal = {Nat Med},

volume = {8},

number = {10},

pages = {1122--1128},

abstract = {Thiazolidinediones (TZDs) are effective therapies for type 2 diabetes, which has reached epidemic proportions in industrialized societies. TZD treatment reduces circulating free fatty acids (FFAs), which oppose insulin actions in skeletal muscle and other insulin target tissues. Here we report that TZDs, acting as ligands for the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma, markedly induce adipocyte glycerol kinase (GyK) gene expression. This is surprising, as standard textbooks indicate that adipocytes lack GyK and thereby avoid futile cycles of triglyceride breakdown and resynthesis from glycerol and FFAs. By inducing GyK, TZDs markedly stimulate glycerol incorporation into triglyceride and reduce FFA secretion from adipocytes. The 'futile' fuel cycle resulting from expression of GyK in adipocytes is thus a novel mechanism contributing to reduced FFA levels and perhaps insulin sensitization by antidiabetic therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid12082115,

title = {Thiazolidinedione activation of peroxisome proliferator-activated receptor gamma can enhance mitochondrial potential and promote cell survival},

author = {Y Lynn Wang and Kenneth A Frauwirth and Shamina M Rangwala and Mitchell A Lazar and Craig B Thompson},

doi = {10.1074/jbc.M204279200},

issn = {0021-9258},

year  = {2002},

date = {2002-08-01},

journal = {J Biol Chem},

volume = {277},

number = {35},

pages = {31781--31788},

abstract = {Thiazolidinediones (TZDs) are widely used for treatment of type 2 diabetes mellitus. Peroxisome proliferator-activated receptor gamma (PPAR gamma) is the molecular target of TZDs and is believed to mediate the apoptotic effects of this class of drugs in a variety of cell types, including B and T lymphocytes. The finding that TZDs induce lymphocyte death has raised concerns regarding whether TZDs might further impair immune functions in diabetics. To address this issue, we investigated the roles of PPAR gamma and TZDs in lymphocyte survival. PPAR gamma was up-regulated upon T cell activation. As previously reported, PPAR gamma agonists induced T cell death in a dose-dependent manner. However, the concentrations of TZD needed to cause T cell death were above those needed to induce PPAR gamma-dependent transcription. Surprisingly, at concentrations that induce optimal transcriptional activation, TZD activation of PPAR gamma protected cells from apoptosis following growth factor withdrawal. The survival-enhancing effects depended on both the presence and activation of PPAR gamma. Measurements of mitochondrial potential revealed that PPAR gamma activation enhanced the ability of cells to maintain their mitochondrial potential. These data indicate that activation of PPAR gamma with TZDs can promote cell survival and suggest that PPAR gamma activation may potentially augment the immune responses of diabetic patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11901161,

title = {Mechanisms regulating adipocyte expression of resistin},

author = {Helen B Hartman and Xiao Hu and Keala X Tyler and Chiraj K Dalal and Mitchell A Lazar},

doi = {10.1074/jbc.M201451200},

issn = {0021-9258},

year  = {2002},

date = {2002-05-01},

journal = {J Biol Chem},

volume = {277},

number = {22},

pages = {19754--19761},

abstract = {Resistin, also known as Adipocyte Secreted Factor (ADSF) and Found in Inflammatory Zone 3 (FIZZ3), is a mouse protein with potential roles in insulin resistance and adipocyte differentiation. The resistin gene is expressed almost exclusively in adipocytes. Here we show that a proximal 264-base pair fragment of the mouse resistin promoter is sufficient for expression in adipocytes. Ectopic expression of the adipogenic transcription factor CCAAT/enhancer-binding protein (C/EBPalpha) was sufficient for expression in non-adipogenic cells. C/EBPalpha binds specifically to a site that is essential for expression of the resistin promoter. Chromatin immunoprecipitation studies of the endogenous gene demonstrated adipocyte-specific association of C/EBPalpha with the proximal resistin promoter in adipocytes but not preadipocytes. C/EBPalpha binding was associated with the recruitment of coactivators p300 and CREB-binding protein and a dramatic increase in histone acetylation in the vicinity of the resistin promoter. The antidiabetic thiazolidinedione (TZD) drug rosiglitazone reduced resistin expression with an ED(50) similar to its K(d) for binding to peroxisome proliferator activated receptor gamma (PPARgamma). Other TZD- and non-TZD PPARgamma ligands also down-regulated resistin expression. However, no functional PPARgamma binding site was found within 6.2 kb of the transcriptional start site, suggesting that if PPARgamma is involved, it is either acting at a long distance from the start site, in an intron, or indirectly. Nevertheless, rosiglitazone treatment selectively decreased histone acetylation at the resistin promoter without a change in occupation by C/EBPalpha, CREB-binding protein, or p300. Thus, adipocyte specificity of resistin gene expression is because of C/EBPalpha binding, leading to the recruitment of transcriptional coactivators and histone acetylation that is characteristic of an active chromatin environment. TZD reduces resistin gene expression at least in part by reducing histone acetylation associated with the binding of C/EBPalpha in mature adipocytes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11981038,

title = {Differential gene regulation by PPARgamma agonist and constitutively active PPARgamma2},

author = {Yong Li and Mitchell A Lazar},

doi = {10.1210/mend.16.5.0825},

issn = {0888-8809},

year  = {2002},

date = {2002-05-01},

journal = {Mol Endocrinol},

volume = {16},

number = {5},

pages = {1040--1048},

abstract = {The PPARgamma is a key adipogenic determination factor. Ligands for PPARgamma such as antidiabetic thiazolidinedione (TZD) compounds are adipogenic, and many adipocyte genes that are activated by TZDs contain binding sites for PPARgamma. Like ligands for other nuclear receptors, TZDs can regulate genes positively or negatively. Here, we sought to understand the importance of positive regulation of gene expression by PPARgamma in adipogenesis. Fusion of the potent viral transcriptional activator VP16 to PPARgamma2 (VP16-PPARgamma) created a transcription factor that constitutively and dramatically activated transcription of PPARgamma-responsive genes in the absence of ligand. Forced expression of VP16-PPARgamma in 3T3-L1 preadipocytes using retroviral vectors led to adipogenesis in the absence of standard differentiating medium or any exogenous PPARgamma ligand. Gene microarray analysis revealed that VP16-PPARgamma induced many of the genes associated with adipogenesis and adipocyte function. Thus, direct up-regulation of gene expression by PPARgamma is sufficient for adipogenesis. TZD-induced adipogenesis up-regulated many of the same genes, although some were divergently regulated, including resistin, whose gene expression was reduced inVP16-PPARgamma adipocytes treated with TZDs. These results show that, although activation of PPARgamma by a heterologous activation domain is sufficient for adipogenesis, it is not equivalent to TZD treatment. This conclusion has important implications for understanding biological effects of the TZDs on adipogenesis and insulin sensitization.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid12019171,

title = {Cooperative function of Aml1-ETO corepressor recruitment domains in the expansion of primary bone marrow cells},

author = {Bruce A Hug and Samuel Y D Lee and Erron L Kinsler and Jinsong Zhang and Mitchell A Lazar},

issn = {0008-5472},

year  = {2002},

date = {2002-05-01},

journal = {Cancer Res},

volume = {62},

number = {10},

pages = {2906--2912},

abstract = {AML1-ETO is an oncoprotein that can promote self-renewal of primary hematopoietic cells by opposing the activity of AML1. Two domains, Nervy-homology(NH) 2 and NH4, have been implicated in the recruitment of corepressors by AML1-ETO, but the relative roles of NH2 and NH4 vary in different cell lines and have not been examined in nonimmortalized cells. Here, we have used a series of differentiation, proliferation, and self-renewal assays in an effort to determine the roles of the NH domains using progenitor-enriched primary bone marrow cells. In these assays, deletion of NH2 or NH4, individually, has a minimal effect on AML1-ETO function, and the mutants retain the ability to promote long-term expansion of cells. In contrast, the double deletion of NH2 and NH4 eliminates the activity of the fusion protein. Thus, the double deletion of NH2 and NH4 produces a functional deficit greater than the sum of the individual deletions. These findings suggest that the NH2 and NH4 domains function cooperatively in the corepressor environment of primary bone marrow cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11867819,

title = {The dawn of the SPPARMs?},

author = {Shamina M Rangwala and Mitchell A Lazar},

doi = {10.1126/stke.2002.121.pe9},

issn = {1525-8882},

year  = {2002},

date = {2002-02-01},

journal = {Sci STKE},

volume = {2002},

number = {121},

pages = {pe9},

abstract = {Thiazolidinediones (TZDs) are used as antidiabetic agents in the treatment of type II diabetes. These compounds are ligands for the nuclear hormone receptor PPARgamma, which is highly expressed in adipose tissue. PPARgamma acts as a molecular switch in the process of fat cell development. The quest for the ideal antidiabetic agent is challenged by the need to develop PPARgamma ligands that improve insulin sensitivity, but do not promote fat cell formation. A newly described PPARgamma ligand may represent an initial step in this direction and could lead to improved agents for treating insulin resistance in type II diabetes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11750858,

title = {Resistin and obesity-associated insulin resistance},

author = {Claire M Steppan and Mitchell A Lazar},

doi = {10.1016/s1043-2760(01)00522-7},

issn = {1043-2760},

year  = {2002},

date = {2002-01-01},

journal = {Trends Endocrinol Metab},

volume = {13},

number = {1},

pages = {18--23},

abstract = {Obesity is a major risk factor for insulin resistance and type 2 diabetes mellitus. Adipocytes secrete numerous substances that might contribute to peripheral insulin sensitivity. These include leptin, tumor necrosis factor alpha, Acrp30/adiponectin/adipoQ and interleukin 6, the potential roles of which are briefly reviewed here. Thiazolidinedione (TZD) antidiabetic drugs regulate gene transcription by binding to peroxisome proliferator activated receptor gamma, a nuclear hormone receptor found at its highest levels in adipocytes. A search for genes that are downregulated by TZDs in mouse adipocytes led to the discovery of an adipose-specific secreted protein called resistin. Resistin circulates in the mouse, with increased levels in obesity, and has effects on glucose homeostasis that oppose those of insulin. Thus, resistin is a potential link between TZDs, obesity and insulin resistance in the mouse. Future studies must address the mechanism of action and biological role of resistin and related family members in mice and humans.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11782439,

title = {Becoming fat},

author = {Mitchell A Lazar},

doi = {10.1101/gad.964002},

issn = {0890-9369},

year  = {2002},

date = {2002-01-01},

journal = {Genes Dev},

volume = {16},

number = {1},

pages = {1--5},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11804585,

title = {Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR},

author = {Wolfgang Fischle and Franck Dequiedt and Michael J Hendzel and Matthew G Guenther and Mitchell A Lazar and Wolfgang Voelter and Eric Verdin},

doi = {10.1016/s1097-2765(01)00429-4},

issn = {1097-2765},

year  = {2002},

date = {2002-01-01},

journal = {Mol Cell},

volume = {9},

number = {1},

pages = {45--57},

abstract = {Histone deacetylases (HDACs) play a key role in regulating eukaryotic gene expression. The HDAC domain, homologous to the yeast repressors RPD3 and HDA1, is considered necessary and sufficient for enzymatic activity. Here, we show that the catalytic domain of HDAC4 interacts with HDAC3 via the transcriptional corepressor N-CoR/SMRT. All experimental conditions leading to the suppression of HDAC4 binding to SMRT/N-CoR and to HDAC3 result in the loss of enzymatic activity associated with HDAC4. In vitro reconstitution experiments indicate that HDAC4 and other class II HDACs are inactive in the context of the SMRT/N-CoR-HDAC3 complex and do not contribute to its enzymatic activity. These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11774944,

title = {An open-label trial of the PPAR-gamma ligand rosiglitazone for active ulcerative colitis},

author = {J D Lewis and G R Lichtenstein and R B Stein and J J Deren and T A Judge and F Fogt and E E Furth and E J Demissie and L B Hurd and C G Su and S A Keilbaugh and M A Lazar and G D Wu},

doi = {10.1111/j.1572-0241.2001.05333.x},

issn = {0002-9270},

year  = {2001},

date = {2001-12-01},

journal = {Am J Gastroenterol},

volume = {96},

number = {12},

pages = {3323--3328},

abstract = {OBJECTIVES: Previous research has demonstrated that ligands for the gamma subtype of peroxisome proliferator-activated receptors (PPARs) reduce inflammation in two different murine models of colitis. This study was designed to examine the potential efficacy of rosiglitazone, a ligand for the gamma subtype of PPARs, as a therapy for active ulcerative colitis.nnMETHODS: Fifteen patients with mild to moderately active ulcerative colitis despite therapy with 5-aminosalicylic acid compounds were enrolled in an open-label study of rosiglitazone (4 mg b.i.d. p.o.) for 12 wk. Thirteen of 15 patients were receiving concomitant therapy with corticosteroids and/or immunomodulator medications. Disease activity was measured with the Disease Activity Index.nnRESULTS: After 12 wk of therapy, four patients (27%) had achieved clinical remission, of whom three (20%) also had an endoscopic remission. Four additional patients (27%) had a clinical response without achieving remission. Two patients were hospitalized with worsened disease activity, and one patient was withdrawn for nephrotic syndrome.nnCONCLUSIONS: These data suggest that ligands for the gamma subtype of PPARs may represent a novel therapy for ulcerative colitis. A double blind, placebo-controlled, randomized trial is warranted.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11473107,

title = {Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen},

author = {C J Phiel and F Zhang and E Y Huang and M G Guenther and M A Lazar and P S Klein},

doi = {10.1074/jbc.M101287200},

issn = {0021-9258},

year  = {2001},

date = {2001-09-01},

journal = {J Biol Chem},

volume = {276},

number = {39},

pages = {36734--36741},

abstract = {Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its mechanisms of action in any of these settings are unknown. We report that valproic acid activates Wntdependent gene expression, similar to lithium, the mainstay of therapy for bipolar disorder. Valproic acid, however, acts through a distinct pathway that involves direct inhibition of histone deacetylase (IC(50) for HDAC1 = 0.4 mm). At therapeutic levels, valproic acid mimics the histone deacetylase inhibitor trichostatin A, causing hyperacetylation of histones in cultured cells. Valproic acid, like trichostatin A, also activates transcription from diverse exogenous and endogenous promoters. Furthermore, valproic acid and trichostatin A have remarkably similar teratogenic effects in vertebrate embryos, while non-teratogenic analogues of valproic acid do not inhibit histone deacetylase and do not activate transcription. Based on these observations, we propose that inhibition of histone deacetylase provides a mechanism for valproic acid-induced birth defects and could also explain the efficacy of valproic acid in the treatment of bipolar disorder.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11509652,

title = {The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3},

author = {M G Guenther and O Barak and M A Lazar},

doi = {10.1128/MCB.21.18.6091-6101.2001},

issn = {0270-7306},

year  = {2001},

date = {2001-09-01},

journal = {Mol Cell Biol},

volume = {21},

number = {18},

pages = {6091--6101},

abstract = {Repression of gene transcription is linked to regulation of chromatin structure through deacetylation of core histone amino-terminal tails. This action is mediated by histone deacetylases (HDACs) that function within active multiprotein complexes directed to the promoters of repressed genes. In vivo, HDAC3 forms a stable complex with the SMRT corepressor. The SMRT-HDAC3 complex exhibits histone deacetylase activity, whereas recombinant HDAC3 is an inactive enzyme. Here we report that SMRT functions as an activating cofactor of HDAC3. In contrast, SMRT does not activate the class II HDAC4, with which it also interacts. Activation of HDAC3 is mediated by a deacetylase activating domain (DAD) that includes one of two SANT motifs present in SMRT. A cognate DAD is present in the related corepressor N-CoR, which can also activate HDAC3. Mutations in the DAD that abolish HDAC3 interaction also eliminate reconstitution of HDAC activity. Using purified components, the SMRT DAD is shown to be necessary and sufficient for activation of HDAC3. Moreover, the DAD is required both for HDAC3 to function enzymatically and for the major repression function of SMRT. Thus, SMRT and N-CoR do not serve merely as platforms for HDAC recruitment but function as an integral component of an active cellular HDAC3 enzyme.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11358969,

title = {Dimerization of resistin and resistin-like molecules is determined by a single cysteine},

author = {R R Banerjee and M A Lazar},

doi = {10.1074/jbc.M103109200},

issn = {0021-9258},

year  = {2001},

date = {2001-07-01},

journal = {J Biol Chem},

volume = {276},

number = {28},

pages = {25970--25973},

abstract = {Resistin is a peptide hormone secreted by adipocytes. Cysteine residues comprise 11 of 94 (12%) amino acids in resistin. The arrangement of these cysteines is unique to resistin and its recently discovered family of tissue-specific secreted proteins, which have been independently termed resistin-like molecules (RELMs) and the FIZZ (found in inflammatory zone) family. Here we show that resistin is a disulfide-linked homodimer that can be converted to a monomer by reducing conditions. The intestine-specific RELM beta has similar characteristics. Remarkably, however, the adipose-enriched RELM alpha is a monomer under non-reducing conditions. We note that RELM alpha lacks a cysteine residue, closest to the cleaved N terminus, that is present in resistin and RELM beta in multiple species. Conversion of this cysteine to alanine abolishes dimerization of resistin. Thus, a single disulfide bond is necessary to connect two resistin subunits in a homodimer. The additional 10 cysteines most likely participate in intramolecular disulfide bonds that define the conserved structure of the family members. The monomeric nature of RELM alpha suggests structural and potentially functional divergence between resistin and this close family member.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11287611,

title = {Inhibition of cellular proliferation through IkappaB kinase-independent and peroxisome proliferator-activated receptor gamma-dependent repression of cyclin D1},

author = {C Wang and M Fu and M D'Amico and C Albanese and J N Zhou and M Brownlee and M P Lisanti and V K Chatterjee and M A Lazar and R G Pestell},

doi = {10.1128/MCB.21.9.3057-3070.2001},

issn = {0270-7306},

year  = {2001},

date = {2001-05-01},

journal = {Mol Cell Biol},

volume = {21},

number = {9},

pages = {3057--3070},

abstract = {The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-regulated nuclear receptor superfamily member. Liganded PPARgamma exerts diverse biological effects, promoting adipocyte differentiation, inhibiting tumor cellular proliferation, and regulating monocyte/macrophage and anti-inflammatory activities in vitro. In vivo studies with PPARgamma ligands showed enhancement of tumor growth, raising the possibility that reduced immune function and tumor surveillance may outweigh the direct inhibitory effects of PPARgamma ligands on cellular proliferation. Recent findings that PPARgamma ligands convey PPARgamma-independent activities through IkappaB kinase (IKK) raises important questions about the specific mechanisms through which PPARgamma ligands inhibit cellular proliferation. We investigated the mechanisms regulating the antiproliferative effect of PPARgamma. Herein PPARgamma, liganded by either natural (15d-PGJ(2) and PGD(2)) or synthetic ligands (BRL49653 and troglitazone), selectively inhibited expression of the cyclin D1 gene. The inhibition of S-phase entry and activity of the cyclin D1-dependent serine-threonine kinase (Cdk) by 15d-PGJ(2) was not observed in PPARgamma-deficient cells. Cyclin D1 overexpression reversed the S-phase inhibition by 15d-PGJ(2). Cyclin D1 repression was independent of IKK, as prostaglandins (PGs) which bound PPARgamma but lacked the IKK interactive cyclopentone ring carbonyl group repressed cyclin D1. Cyclin D1 repression by PPARgamma involved competition for limiting abundance of p300, directed through a c-Fos binding site of the cyclin D1 promoter. 15d-PGJ(2) enhanced recruitment of p300 to PPARgamma but reduced binding to c-Fos. The identification of distinct pathways through which eicosanoids regulate anti-inflammatory and antiproliferative effects may improve the utility of COX2 inhibitors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11238912,

title = {Determinants of CoRNR-dependent repression complex assembly on nuclear hormone receptors},

author = {X Hu and Y Li and M A Lazar},

doi = {10.1128/MCB.21.5.1747-1758.2001},

issn = {0270-7306},

year  = {2001},

date = {2001-03-01},

journal = {Mol Cell Biol},

volume = {21},

number = {5},

pages = {1747--1758},

abstract = {Ligand-dependent exchange of coactivators and corepressors is the fundamental regulator of nuclear hormone receptor (NHR) function. The interaction surfaces of coactivators and corepressors are similar but distinct enough to allow the ligand to function as a switch. Multiple NHRs share features that allow corepressor binding, and each of two distinct corepressors (N-CoR and SMRT) contains two similar CoRNR motifs that interact with NHRs. Here we report that the specificity of corepressor-NHR interaction is determined by the individual NHR interacting with specific CoRNR boxes within a preferred corepressor. First, receptors have distinct preferences for CoRNR1 versus CoRNR2. For example, the retinoic acid receptor binds CoRNR1, while RXR interacts almost exclusively with CoRNR2. Second, the NHR preference for N-CoR or SMRT is due to differences in CoRNR1 but not CoRNR2. Moreover, within a single corepressor, affinity for different NHRs is determined by distinct regions flanking CoRNR1. The highly specific determinants of NHR-corepressor interaction and preference suggest that repression is regulated by the permissibility of selected receptor-CoRNR-corepressor combinations. Interestingly, different NHR surfaces contribute to binding of CoRNR1 and CoRNR2, suggesting a model to explain corepressor binding to NHR heterodimers.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}