Increased activity of lipoprotein lipase (LPL) may explain the hypotriglyceridemic effects of fibrates, thiazolidinediones and fatty acids, which are known activators (and/or ligands) of the various peroxisome proliferator‐activated receptors (PPARs). Treatment with compounds which activate preferentially PPARalpha, such as fenofibrate, induced LPL expression exclusively in rat liver. In contrast, the antidiabetic thiazolidinedione BRL 49653, a high affinity ligand for PPARgamma, had no effect on liver, but induced LPL expression in rat adipose tissue. In the hepatocyte cell line AML‐12, fenofibric acid, but not BRL 49653, induced LPL mRNA, whereas in 3T3‐L1 preadipocytes, the PPARgamma ligand induced LPL mRNA levels much quicker and to a higher extent than fenofibric acid. In both the in vivo and in vitro studies, inducibility by either PPARalpha or gamma activators, correlated with the tissue distribution of the respective PPARs: an adipocyte‐restricted expression of PPARgamma, whereas PPARalpha was expressed predominantly in liver. A sequence element was identified in the human LPL promoter that mediates the functional responsiveness to fibrates and thiazolidinediones. Methylation interference and gel retardation assays demonstrated that a PPARalpha or gamma and the 9‐cis retinoic acid receptor (RXR) heterodimers bind to this sequence −169 TGCCCTTTCCCCC −157. These data provide evidence that transcriptional activation of the LPL gene by fibrates and thiazolidinediones is mediated by PPAR‐RXR heterodimers and contributes significantly to their hypotriglyceridemic effects in vivo. Whereas thiazolidinediones predominantly affect adipocyte LPL production through activation of PPARgamma, fibrates exert their effects mainly in the liver via activation of PPARalpha.
An understanding of the differences and similarities of the retinoid X receptor (RXR) and retinoic acid receptor (RAR) systems requires knowledge of the diversity of their family members, their patterns of expression, and their pharmacological response to ligands. In this paper we report the isolation of a family of mouse RXR genes encoding three distinct receptors (RXRa, p, and y). They are closely related to each other in their DNAand ligand-binding domains but are quite divergent from the RAR subfamily in both structure and ligand specificity. Recently, we demonstrated that all-trans retinoic acid (RA) serves as a "pro-hormone" to the isomer 9-cis RA, which is a high-affinity ligand for the human RXRa. We extend those findings to show that 9-cis RA is also "retinoid X" for mouse RXRa, p, and y. Trans-activation analyses show that although all three RXRs respond to a variety of endogenous retinoids, 9-cis RA is their most potent ligand and is up to 40-fold more active than all-trans RA. Northern blot and in situ hybridization analyses define a broad spectrum of expression for the RXRs, which display unique patterns and only partially overlap themselves and the RARs. This study suggests that the RXR family plays critical roles in diverse aspects of development, from embryo implantation to organogenesis and central nervous system differentiation, as well as in adult physiology.[Key Words: RXRa, p, and 7; vitamin A metabolism; RXR ligands; retinoid receptors in development; nuclear receptor superfamily; 9-cis retinoic acid]
The development of colorectal cancer, one of the most frequent cancers, is influenced by prostaglandins and fatty acids. Decreased prostaglandin production, seen in mice with mutations in the cyclooxygenase 2 gene or in animals and humans treated with cyclooxygenase inhibitors, prevents or attenuates colon cancer development. There is also a strong correlation between the intake of fatty acids from animal origin and colon cancer. Therefore, the peroxisome proliferator-activated receptor gamma (PPARgamma), a downstream transcriptional mediator for prostaglandins and fatty acids which is highly expressed in the colon may be involved in this process. Activation of PPARgamma by two different synthetic agonists increased the frequency and size of colon tumors in C57BL/6J-APCMin/+ mice, an animal model susceptible to intestinal neoplasia. Tumor frequency was only increased in the colon, and did not change in the small intestine, coinciding with the colon-restricted expression of PPARgamma. Treatment with PPARgamma agonists increased beta-catenin levels both in the colon of C57BL/61-APCMin/+ mice and in HT-29 colon carcinoma cells. Genetic abnormalities in the Wnt/wingless/APC pathway, which enhance the transcriptional activity of the beta-catenin-T-cell factor/lymphoid enhancer factor 1 transcription complex, often underly the development of colon tumors. Our data indicate that PPARgamma activation modifies the development of colon tumors in C57BL/61-APCMin/+ mice.
Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.
Evidence exists to suggest that human cytomegalovirus (hCMV) may opportunistically use retinoic acid (RA) to advance its own replication, in which transcriptional activation of the viral major immediate-early promoter is a crucial control point. We demonstrate that the enhancer of the viral promoter contains three RA-response-elements that cooperate in mediating RA activation. These elements are direct repeats of two sequence motifs separated by 2 bp (DR2 site, REa) and 5 bp (DR5 sites, REb and c). DNA-binding experiments revealed that each of these elements bind RA receptor (RAR)-retinoid X receptor (RXR) heterodimers more efficiently than either homodimer. Apparent equilibrium dissociation constants of RAR-RXR heterodimers for sites REa, REb, and REc were estimated to be 5 nm, 10 nm, and 20 nm, respectively. The level of contribution of each of these elements to RA inducibility correlated with the strength of binding by RAR-RXR heterodimers to each site. These experiments demonstrate that RAR and RXR are necessary for RA responsiveness of the viral promoter. Using synthetic RA analogs, which selectively activate RARs and RXRs, the RAR partner within the heterodimeric complex appeared to be sufficient while the RXR partner was insufficient to independently activate transcription. However, joint activation of RARs and RXRs indicated that RXRs (in the presence of a transcriptionally active RAR) could contribute to transactivation. This restricted co-dependent ligand activation of RXR varied depending on the particular response element and the cell context. These studies further indicate that signaling of retinoid receptors (in particular RAR) by RA plays an important role in modulating hCMV infection.
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