Identification of a Nonsteroidal Liver X Receptor Agonist through Parallel Array Synthesis of Tertiary Amines

Collins, Jon L.; Fivush, Adam M.; Watson, Michael A.; Galardi, Cristin M.; Lewis, Michael C.; Moore, Linda B.; Parks, Derek J.; Wilson, Joan G.; Tippin, Tim K; Binz, Jane G; Plunket, Kelli D.; Morgan, Daniel G.; Beaudet, Elizabeth J.; Whitney, Karl; Kliewer, Steven A.; Willson, Timothy M.

doi:10.1021/jm0255116

Cited by 390 publications

(268 citation statements)

References 23 publications

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“…Surprisingly, expression of Leptin gene was 2.5-fold higher in SC fat of LXRα −/− mice compared with WT mice, whereas no differences were observed between groups in gonadal fat. Recent reports have shown that ectopic Ucp1 expression in WAT (24) can appear because of differentiation of white fat cells into brown fat cells in the WAT (4,25). A 10-fold increase associated with a fivefold decrease of Ucp1 expression was observed in gonadal vs. SC fat, respectively, in LXRα −/− mice compared with WT mice ( Fig.…”

Section: Increased Subcutaneous Leptin Expression and Gonadal Fat Ucp1mentioning

confidence: 81%

Both liver-X receptor (LXR) isoforms control energy expenditure by regulating Brown Adipose Tissue activity

Korach-André

Archer

Barros

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Brown adipocytes are multilocular lipid storage cells that play a crucial role in nonshivering thermogenesis. Uncoupling protein 1 (UCP1) is a unique feature of brown fat cells that allows heat generation on sympathetic nervous system stimulation. As conventional transcriptional factors that are activated in various signaling pathways, liver-X receptors (LXRs) play important roles in many physiological processes. The role of LXRs in the regulation of energy homeostasis remains unclear, however. Female WT, LXRαβ −/− , LXRα −/− , and LXRβ −/− mice were fed with either a normal diet (ND) or a high-carbohydrate diet (HCD) supplemented with or without GW3965-LXR agonist. LXRαβ −/− mice exhibited higher energy expenditure (EE) as well as higher UCP1 expression in brown adipose tissue (BAT) compared with WT mice on the HCD. In addition, long-term treatment of WT mice with GW3965 showed lower EE at thermoneutrality (30°C) and lower Ucp1 expression level in BAT. Furthermore, H&E staining of the BAT of LXRαβ −/− mice exhibited decreased lipid droplet size compared with WT mice on the HCD associated with a more intense UCP1-positive reaction. Quantification of triglyceride (TG) content in BAT showed lower TG accumulation in LXRβ −/− mice compared with WT mice. Surprisingly, GW3965 treatment increased TG content (twofold) in the BAT of WT and LXRα −/− mice but not in LXRβ −/− mice. Furthermore, glucose transporter (GLUT4) in the BAT of LXRα −/− and LXRβ −/− mice was sixfold and fourfold increased, respectively, compared with WT mice on the ND. These findings suggest that LXRα as well as LXRβ could play a crucial role in the regulation of energy homeostasis in female mice and may be a potential target for the treatment of obesity and energy regulation.

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Section: Increased Subcutaneous Leptin Expression and Gonadal Fat Ucp1mentioning

confidence: 81%

Both liver-X receptor (LXR) isoforms control energy expenditure by regulating Brown Adipose Tissue activity

Korach-André

Archer

Barros

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…An initial screening of possible ligands for these receptors revealed that T-0901317 and GW3965 (see Fig. 1 for chemical structures), both previously reported as agonists of mammalian LXRs [23,24], also robustly activated the two Xenopus LXRs, as well as the zfLXR. T-0901317 was selected as the reference 'maximal' activator for the vertebrate LXRs in this study; the maximal activation of all other tested compounds at these receptors was then compared to T-0901317.…”

Section: Ligand Specificity Of Vertebrate Lxrsmentioning

confidence: 99%

“…In mammals, GW3965 has been reported as a selective ligand for LXRs relative to other NRs (although it does not distinguish between LXRα and LXRβ) [23]. We also tested GW3965 on Xenopus laevis and zebrafish FXRs, vitamin D receptors (VDRs, NR1I1), and pregnane X receptors (PXRs, NR1I2) and found no effect of this compound on these receptors; in contrast, T-0901317 activated the zebrafish FXR in the low micromolar range (E.J.…”

Section: Ligand Specificity Of Vertebrate Lxrsmentioning

confidence: 99%

Ligand specificity and evolution of liver X receptors

Reschly

Ni²,

Welsh³

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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Liver X receptors (LXRs) are key regulators of lipid and cholesterol metabolism in mammals. Little is known, however, about the function and evolution of LXRs in non-mammalian species. The present study reports the cloning of LXRs from African clawed frog (Xenopus laevis), Western clawed frog (Xenopus tropicalis), and zebrafish (Danio rerio), and their functional characterization and comparison with human and mouse LXRs. Additionally, an ortholog of LXR in the chordate invertebrate Ciona intestinalis was cloned and functionally characterized. Ligand specificities of the frog and zebrafish LXRs were very similar to LXRα and LXRβ from human and mouse. All vertebrate LXRs studied were activated robustly by the synthetic ligands T-0901317 and GW3965 and by a variety of oxysterols. In contrast, Ciona LXR was not activated by T-0901317 or GW3965 but was activated by a limited number of oxysterols, as well as some androstane and pregnane steroids. Pharmacophore analysis, homology modeling, and docking studies of Ciona LXR predict a receptor with a more restricted ligand-binding pocket and less intrinsic disorder in the ligand-binding domain compared to vertebrate LXRs. The results suggest that LXRs have a long evolutionary history, with vertebrate LXRs diverging from invertebrate LXRs in ligand specificity.

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“…Next we evaluated whether pharmacological activation of LXRs using synthetic ligands could prevent matrix degradation in human cartilage. A highly selective LXR ligand, GW3965 (18), which has been broadly used in the LXR research field, was chosen for this study. An ex vivo articular cartilage explant model that allows investigation of the direct effects of proinflammatory cytokines such as IL-1β and OSM on cartilage was used.…”

Section: Deletion Of Lxrβ Gene In Mice Increases Cartilage Matrix Catmentioning

confidence: 99%

LXR modulation blocks prostaglandin E ₂ production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model

Rivera-Bermudez

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Osteoarthritis (OA), the most common arthritic condition in humans, is characterized by the progressive degeneration of articular cartilage accompanied by chronic joint pain. Inflammatory mediators, such as cytokines and prostaglandin E 2 (PGE 2 ) that are elevated in OA joints, play important roles in the progression of cartilage degradation and pain-associated nociceptor sensitivity. We have found that the nuclear receptor family transcription factors Liver X Receptors (LXRα and -β) are expressed in cartilage, with LXRβ being the predominant isoform. Here we show that genetic disruption of Lxrβ gene expression in mice results in significantly increased proteoglycan (aggrecan) degradation and PGE 2 production in articular cartilage treated with IL-1β, indicating a protective role of LXRβ in cartilage. Using human cartilage explants, we found that activation of LXRs by the synthetic ligand GW3965 significantly reduced cytokine-induced degradation and loss of aggrecan from the tissue. Furthermore, LXR activation dramatically inhibited cytokine-induced PGE 2 production by human osteoarthritic cartilage as well as by a synovial sarcoma cell line. These effects were achieved at least partly by repression of the expression of ADAMTS4, a physiological cartilage aggrecanase, and of cyclooxygenase-2 and microsomal prostaglandin E synthase-1, key enzymes in the PGE 2 synthesis pathway. Consistent with our in vitro observations, oral administration of GW3965 potently alleviated joint pain in a rat meniscal tear model of osteoarthritis.cartilage | pain | prostaglandin E2 C ytokines and growth factors play significant roles in the physiology of synovial joints. Increased catabolism and/or decreased anabolism of cartilage macromolecules can result in a net loss of matrix components and deterioration of the structural and functional properties that characterize osteoarthritis (OA) (1, 2). The cartilage matrix is degraded mainly by proteases produced by chondrocytes. The destructive enzymes, such as ADAMTS4 (aggrecanase-1) and matrix metallopeptidase 13 (MMP-13, collagenase-3), are up-regulated by inflammatory cytokines such as IL-1β and oncostatin M (OSM) (2-4). Prostaglandin E 2 (PGE 2 ) is a prostanoid that is derived from arachidonic acid released from membranes by phospholipase A 2 . Elevated levels of PGE 2 in OA joints have been reported (2, 5). Cyclooxygenase-2 (COX-2) and microsomal PGE synthase 1 (mPGES-1) are the main enzymes in PGE 2 synthesis during inflammation. PGE 2 contributes to the chronic disabling pain of arthritis by increasing sensitivity of peripheral nociceptive primary afferent neurons and central nociceptive neurons (6). In addition, a major role for PGE 2 during inflammation-mediated matrix degradation has been documented using animal models (7) and human cartilage explant cultures (5, 8).The Liver X Receptors (LXRα/NR1H3 and LXRβ/NR1H2) are oxysterol-activated transcription factors of the nuclear receptor family that play an important role in the control of cellular and whole-body cholesterol homeo...

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Identification of a Nonsteroidal Liver X Receptor Agonist through Parallel Array Synthesis of Tertiary Amines

Cited by 390 publications

References 23 publications

Both liver-X receptor (LXR) isoforms control energy expenditure by regulating Brown Adipose Tissue activity

Both liver-X receptor (LXR) isoforms control energy expenditure by regulating Brown Adipose Tissue activity

Ligand specificity and evolution of liver X receptors

LXR modulation blocks prostaglandin E ₂ production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model

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Identification of a Nonsteroidal Liver X Receptor Agonist through Parallel Array Synthesis of Tertiary Amines

Cited by 390 publications

References 23 publications

Both liver-X receptor (LXR) isoforms control energy expenditure by regulating Brown Adipose Tissue activity

Both liver-X receptor (LXR) isoforms control energy expenditure by regulating Brown Adipose Tissue activity

Ligand specificity and evolution of liver X receptors

LXR modulation blocks prostaglandin E 2 production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model

Contact Info

Product

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LXR modulation blocks prostaglandin E ₂ production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model