Metabolic Effects of Rexinoids: Tissue-Specific Regulation of Lipoprotein Lipase Activity

Davies, Peter J.; Berry, Stacey A.; Shipley, Gregory L.; Eckel, Robert H.; Hennuyer, Nathalie; Crombie, Diane L.; Ogilvie, Kathleen M.; Peinado-Onsurbe, Júlia; Fiévet, Catherine; Leibowitz, Mark D.; Heyman, Richard A.; Auwerx, Johan

doi:10.1124/mol.59.2.170

Cited by 85 publications

(61 citation statements)

References 38 publications

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“…It is interesting to note that despite the increase in triglyceride levels, hyperglycemia was reduced dose-dependently. This observation is strikingly similar to the previous report on the effects of RXR agonists (24).…”

Section: Discussionsupporting

confidence: 82%

Antidiabetic Action of a Liver X Receptor Agonist Mediated By Inhibition of Hepatic Gluconeogenesis

Cao¹,

Liang²,

Broderick³

et al. 2003

Journal of Biological Chemistry

264

197

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The oxysterol receptors LXR (liver X receptor)-␣ and LXR␤ are nuclear receptors that play a key role in regulation of cholesterol and fatty acid metabolism. We found that LXRs also play a significant role in glucose metabolism. Treatment of diabetic rodents with the LXR agonist, T0901317, resulted in dramatic reduction of plasma glucose. In insulin-resistant Zucker (fa/fa) rats, T0901317 significantly improved insulin sensitivity. Activation of LXR did not induce robust adipogenesis but rather inhibited the expression of several genes involved in hepatic gluconeogenesis, including phosphoenolpyruvate carboxykinase (PEPCK). Hepatic glucose output was dramatically reduced as a result of this regulation. Nuclear run-on studies indicated that transcriptional repression was primarily responsible for the inhibition of PEPCK by the LXR agonist. In addition, we show that the regulation of the liver gluconeogenic pathway by LXR agonists was a direct effect on hepatocytes. These data not only suggest that LXRs are novel targets for diabetes but also reveal an unanticipated role for these receptors, further linking lipid and glucose metabolism.Type II diabetes mellitus is a prevalent metabolic disease in developed countries, with insufficient therapies for treatment and prevention (1, 2). Studies in recent years have suggested that nuclear receptors are intimately linked to the pathophysiology of diabetes. The antidiabetic thiazolidinediones have been identified as ligands of proxisome proliferator-activated receptor ␥ (PPAR␥) 1 (3, 4). Retinoid X receptor (RXR) ligands have also been shown to lower plasma glucose levels in rodent diabetic models (3-5).Originally identified as orphan members of the nuclear receptor superfamily, liver X receptors exist as two isoforms, LXR␣ and LXR␤. The two isoforms display distinct patterns of expression with LXR␣ being primarily expressed in liver, intestine, and kidney, whereas LXR␤ is expressed ubiquitously (6). Oxysterols were identified as the putative physiological ligands for the LXRs (7), and additional studies have demonstrated that these receptors act as sensors for these cholesterol metabolites and are essential components of a physiological feedback loop regulating cholesterol metabolism and transport (8). Consistent with their role in regulation of these metabolic pathways, several LXR-regulated genes involved in lipid metabolism and cholesterol transport have been identified including ABCA1, ABCG1, ABCG5, ABCG8, ApoE, CETP, Cyp7a, LPL, SREBP1c, and FAS (8 -14).As a result of the close relationship between lipid and carbohydrate metabolism, we examined the potential role LXRs may play in glucose homeostasis by using a specific LXR agonist, T0901317, (11) in rodent models of diabetes. Our findings indicated that T0901317 dose-dependently lowered plasma glucose level in both db/db and Zucker diabetic fatty (ZDF) rat models. In the fa/fa insulin-resistant rat model, T0901317 significantly improved insulin sensitivity. Examination of the liver gluconeogenesis pathway revealed dra...

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Section: Discussionsupporting

confidence: 82%

Antidiabetic Action of a Liver X Receptor Agonist Mediated By Inhibition of Hepatic Gluconeogenesis

Cao¹,

Liang²,

Broderick³

et al. 2003

Journal of Biological Chemistry

264

197

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“…A striking example of such distinctive effects was provided recently by the differential tissue-specific regulation of lipoprotein lipase gene expression by RXR (24) and PPAR␥ (25) agonists in adipose tissue and muscle. These differential regulatory effects can be attributed to the capacity of RXR to form permissive heterodimers with a wide range of nuclear receptors, endowing them with ''broad-spectrum'' activity, touching numerous physiological processes.…”

Section: Resultsmentioning

confidence: 99%

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

Claudel

Leibowitz

Fiévet

et al. 2001

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

Self Cite

273

175

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A common feature of many metabolic pathways is their control by retinoid X receptor (RXR) heterodimers. Dysregulation of such metabolic pathways can lead to the development of atherosclerosis, a disease influenced by both systemic and local factors. Here we analyzed the effects of activation of RXR and some of its heterodimers in apolipoprotein E ؊͞؊ mice, a well established animal model of atherosclerosis. An RXR agonist drastically reduced the development of atherosclerosis. In addition, a ligand for the peroxisome proliferator-activated receptor (PPAR)␥ and a dual agonist of both PPAR␣ and PPAR␥ had moderate inhibitory effects. Both RXR and liver X receptor (LXR) agonists induced ATP-binding cassette protein 1 (ABC-1) expression and stimulated ABC-1-mediated cholesterol efflux from macrophages from wild-type, but not from LXR␣ and ␤ double ؊͞؊, mice. Hence, activation of ABC-1-mediated cholesterol efflux by the RXR͞LXR heterodimer might contribute to the beneficial effects of rexinoids on atherosclerosis and warrant further evaluation of RXR͞LXR agonists in prevention and treatment of atherosclerosis. R etinoid X receptors (RXRs) are ubiquitously expressed nuclear receptors that heterodimerize with a number of other receptors (e.g., thyroid hormone receptor, vitamin D receptor, retinoic acid receptors, etc.; refs. 1 and 2). The elucidation of RXRs biological activity has advanced significantly through the characterization of rexinoids, high-affinity selective synthetic ligands for RXRs (1, 2). The use of rexinoids led to the demonstration that RXRs are active and permissive signaling molecules in heterodimers with the farnesol X receptor (FXR) [or bile acid receptor (BAR)], the liver X receptors (LXRs), and the peroxisome proliferatoractivated receptors (PPARs). The simultaneous activation of several permissive heterodimers underlies in part RXRs pleiotropic functions, affecting numerous receptor signaling pathways, and ranges from the control of cell proliferation, differentiation, and apoptosis (3) to the regulation of glucose and lipid metabolism (4). This pivotal role of the various permissive RXR heterodimers is in fact an emerging theme in multiple metabolic pathways. Heterodimers between RXR and PPAR␥, PPAR␣, LXR␣, and FXR͞BAR respectively inf luence glucose, triglyceride, cholesterol, and bile acid homeostasis. Dysregulation of these homeostatic control pathways can result in common metabolic disorders such as obesity, type 2 diabetes, and hyperlipidemia, which are often complicated by the development of atherosclerosis.In view of the potential implication of RXRs in various metabolic pathways implicated in atherosclerosis, we studied whether modulating the activity of these receptors or of some of their heterodimers affects the development of atherosclerosis in apolipoprotein (apo)E-deficient mice. We demonstrate here that the administration of rexinoids significantly attenuates atherosclerosis development, and we show that this effect might be linked to the activation of reverse cholesterol transpor...

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“…Although bexarotene failed to increase overall survival as a single agent, subsets of patients responded to the drug, with highgrade hypertriglyceridemia identified as a biomarker of efficacy. Side effects of hypothyroidism and hypertriglyceridemia are hallmarks of RAR binding, and these toxicities have led to concern and reluctance to undertake further clinical development of rexinoids, especially for cancer prevention (10,11).…”

Section: Introductionmentioning

confidence: 99%

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

Cao

Royce

Risingsong

et al. 2016

Cancer Prevention Research

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LG101506 was originally synthesized to overcome some of the undesirable side effects of rexinoids. We compared the anticarcinogenic action of LG101506 and LG100268 and for the first time showed that both drugs are useful for prevention of lung cancer in A/J mice. These molecules markedly reduced tumor number, tumor size, and total tumor burden, when chronically administered to A/J mice that had been initiated with the mutagenic carcinogen, vinyl carbamate. Moreover, LG100268 synergized with the histone deacetylase inhibitor, vorinostat, for prevention of experimental lung cancer and enhanced the effect of carboplatin/paclitaxel for treatment of experimental lung cancer. Both rexinoids diminished the percentage of high-grade, highly malignant adenocarcinomas found at autopsy. In cell culture studies, the rexinoids exhibited potent anti-inflammatory properties at nanoMolar concentrations. These drugs suppressed the ability of lipopolysaccharide to stimulate the synthesis and secretion of nitric oxide and inflammatory cytokines and chemokines, such as IL6, IL1b, CXCL2, and CSF3, in macrophage-like RAW264.7 cells. The present results suggest that LG100268, LG101506, or a related rexinoid may have useful clinical applications in the field of oncology. Cancer Prev Res; 9(1);

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Metabolic Effects of Rexinoids: Tissue-Specific Regulation of Lipoprotein Lipase Activity

Cited by 85 publications

References 38 publications

Antidiabetic Action of a Liver X Receptor Agonist Mediated By Inhibition of Hepatic Gluconeogenesis

Antidiabetic Action of a Liver X Receptor Agonist Mediated By Inhibition of Hepatic Gluconeogenesis

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

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