Biological Characterization of a Heterodimer-Selective Retinoid X Receptor Modulator: Potential Benefits for the Treatment of Type 2 Diabetes

Leibowitz, Mark D.; Ardecky, Robert; Boehm, Marcus F.; Broderick, Carol L.; Carfagna, Mark A.; Crombie, Diane L.; D'Arrigo, Jennifer; Etgen, Garrett J.; Faul, Margaret M.; Grese, Timothy A.; Havel, Henry A.; Hein, N; Heyman, Richard A.; Jolley, D; Klausing, Kay; Li, Sha; Mais, Dale E.; Mapes, Christopher M.; Marschke, Keith B.; Michellys, Pierre‐Yves; Montrose‐Rafizadeh, Chahrzad; Ogilvie, Kathleen M.; Pascual, Bernadette; Rungta, Deepa; Tyhonas, John S.; Urcan, Mary S.; Wardlow, M.L.; Yumibe, Nathan; Reifel‐Miller, Anne

doi:10.1210/en.2005-0690

Cited by 71 publications

(55 citation statements)

References 38 publications

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“…AP-1 is a rather ubiquitous inflammatory transcription factor, and it is responsible for the regulation of a large number of genes, including MMP-3, which were unaffected by LG268 treatment. Previous studies characterizing LG268 (41)(42)(43) indicated that treatment with this rexinoid activates a limited number of RXR-containing NHR dimers, including RXR-RXR, RXR-farnesoid X receptor, RXR-liver X receptor, RXR-peroxisome proliferator-activated receptor ␣ [PPAR␣], and RXR-PPAR␥. In reviewing the literature, we found substantial data linking specific ligands for PPAR␥ to inhibition of MMP production and therapeutic activity in models of arthritis (44)(45)(46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

Regulation of matrix metalloproteinase gene expression by a retinoid X receptor–specific ligand

Burrage¹,

Huntington²,

Sporn³

et al. 2007

Arthritis & Rheumatism

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Objective. To evaluate the effects of LG100268 (LG268), a synthetic ligand for the nuclear hormone receptor retinoid X receptor, on the expression of matrix metalloproteinase 1 (MMP-1) and MMP-13 induced by proinflammatory cytokines in a chondrocyte model.Methods. SW-1353 human chondrosarcoma cells were used to study the effects of LG268 on interleukin-1␤ (IL-1␤)-stimulated MMP production and collagen degradation. Gene expression was determined by quantitative real-time reverse transcriptionpolymerase chain reaction, and protein levels were determined by Western blot analysis. Collagen degradation was determined by an in vitro matrix destruction assay. The effects of LG268 on nuclear protein binding and histone acetylation were determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assay, respectively.Results.LG268 treatment specifically antagonized the IL-1␤-mediated induction of MMP-1 and MMP-13 heterogeneous nuclear RNA, messenger RNA, and protein. The inhibitory effect of LG268 was found to be due to a decrease in the rate of MMP-1 and MMP-13 transcription.LG268 treatment also prevented the in vitro degradation of a type I collagen matrix by IL-1␤-treated SW-1353 cells. The inhibitory effect of LG268 on MMP-1 and MMP-13 transcription appears to be mediated, at least in part, through modulation of histone modification in regions of the MMP-1 and MMP-13 promoters that contain binding sites for activator protein 1 transcription factors.Conclusion. These data indicate that LG268 treatment selectively inhibits inflammatory cytokineinduced production of MMP-1 and MMP-13 at the level of gene transcription and blocks collagen destruction by proinflammatory cytokine-stimulated chondrocytic cells. This study is among the first to describe how rexinoids affect gene expression, and the findings suggest that the rexinoid class of compounds may have a future role in preventing the irreversible collagen destruction seen in the arthritides.The destruction of joint tissues that is a hallmark of rheumatoid arthritis (RA) and osteoarthritis (OA) is mediated largely by members of the matrix metalloproteinase (MMP) family of enzymes (1-3). At low expression levels, these zinc-dependent endopeptidases maintain connective tissue homeostasis in a wide range of biologic functions (4). However, abnormally high levels of MMP expression have been linked to multiple pathologic states, including tumor invasion, atherosclerosis, and the arthritides (4). In humans, the MMP family currently encompasses 23 unique members, which degrade all constituents of the extracellular matrix (ECM) (5). The MMPs can be subdivided into 6 main classes (1,4,5), consisting of the collagenases (MMPs 1, 8, and 13), the gelatinases (MMPs 2 and 9), the stromelysins (MMPs 3, 10, and 11), the matrilysins (MMPs 7 and 26), the membrane-type MMPs (MMPs 14,15,16,17,24,and 25), and a diverse subgroup.The collagenase subgroup is unique in its ability to cleave fibrillar collagens, and their enzymatic activity represents a rate-limiting step...

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Section: Discussionmentioning

confidence: 99%

Regulation of matrix metalloproteinase gene expression by a retinoid X receptor–specific ligand

Burrage¹,

Huntington²,

Sporn³

et al. 2007

Arthritis & Rheumatism

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“…However, another insulin pathway, namely that involving PKCζ, is also involved in translocation of SLC2A4 [16]; it was inhibited in the presence of TNFα, but was not restored by T0901317. Accordingly, synthetic NR1HR agonists have been reported to improve glucose tolerance in genetic and dietary models of type 2 diabetes [6,8] and to increase glucose-induced insulin secretion by islets [7], very similar effects to those elicited by thiazolidinediones [34] and synthetic activators of RXR [35]. Moreover, NR1HR agonist treatment suppresses hepatic gluconeogenesis [6], inhibits synthesis of proinflammatory cytokines [36] and induces desirable changes in cholesterol metabolism [37], favourable features for a potential drug against diabetes.…”

Section: Discussionmentioning

confidence: 99%

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

et al. 2006

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Aims/hypothesis The nuclear receptors, including nuclear receptor subfamily 1, group H, member 3 (NR1HR, also known as liver X receptor [LXR]), are sensors of cholesterol metabolism and lipid biosynthesis that have recently been proposed as insulin sensitisers. TNFα has been described as a link between obesity and the development of insulin resistance, an important contributor to the pathogenesis of type 2 diabetes. Therefore, we decided to investigate the ability of NR1HR agonists to ameliorate TNFα-induced insulin resistance in brown adipocytes. Methods Primary brown adipocytes from rat fetuses, and from wild-type neonate mice and neonate mice deficient in the gene encoding protein tyrosine phosphatase-1B (Ptpn1, also known as Ptp1b) were cultured in the absence or presence of TNFα and different nuclear receptor agonists. Among them, the unrelated NR1HR ligands T0901317, GW3965 and (22R)-hydroxycholesterol were tested. After insulin stimulation, glucose uptake and solute carrier family 2 (facilitated glucose transporter), member 4 (SLC2A4, formerly known as GLUT4) translocation were measured. Next the insulin signalling cascade was determined by submitting cells to lysis, immunoprecipitation and immunoblotting. Results NR1HR agonists ameliorate TNFα-induced insulin resistance restoring completely insulin-stimulated glucose uptake and SLC2A4 translocation to plasma membrane. This effect is parallel to the recovery of the insulin cascade insulin receptor/IRS-2/phosphatidylinositol 3-kinase/protein kinase B, and could be due to the fact that T0901317 prevents the increase of PTPN1 production and phosphatase activity produced by TNFα. In this regard, Ptpn1-deficient brown adipocytes showed protection against insulin resistance by TNFα. Moreover, we observed that T0901317 produced in itself a significant increase over basal glucose uptake consistent with an increase of SLC2A4 protein content in plasma membrane, attributable to the activation of protein kinase ζ and/or the increase of Slc2a4 expression. Conclusions/interpretation Nuclear receptors NR1HR are interesting potential targets for drug treatment of insulin resistance. Keywords

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“…Along the same line, the poorly active rexinoid HX600 acts as an efficient activator of RXRα-and RXRγ -Nur77/NR4A1 dimers, but not of RXRβ-Nur77 dimers, the latter feature being in line with the reported inability of RXRβ to dimerize with Nurr1/NR4A2 95 . Interestingly, the rexinoid LG101506 activates selectively RXR-PPARγ heterodimers, but not RXR-RAR or RXR-LXR heterodimers 15 . In agreement with the predicted biological consequences of PPARγ activation, this compound lowered significantly blood glucose levels in genetically diabetic mice and did not increase blood triglyceride levels in Sprague-Dawley rats…”

Section: Towards Heterodimer-specific Rexinoidsmentioning

confidence: 98%

Retinoid X receptors: common heterodimerization partners with distinct functions

Lefèbvre

Benomar²,

Staels

2010

Trends in Endocrinology & Metabolism

264

224

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Biological Characterization of a Heterodimer-Selective Retinoid X Receptor Modulator: Potential Benefits for the Treatment of Type 2 Diabetes

Cited by 71 publications

References 38 publications

Regulation of matrix metalloproteinase gene expression by a retinoid X receptor–specific ligand

Regulation of matrix metalloproteinase gene expression by a retinoid X receptor–specific ligand

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

Retinoid X receptors: common heterodimerization partners with distinct functions

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