Rxr Functional Activities

Insights in specific RXR activity come from loss of function experiments in mouse lacking RXR alleles, and from gain of function experiments in mice treated with RXR specific agonists. The first approach demonstrates the confounding actions of RXR on the permissive partner signaling pathways; the second may more specifically addresses the rexinoid pathway in vivo, assuming that a natural ligand for RXR do exist in vivo. Independently of the physiological questions, this latter approach is essential for determining the range of possible therapeutic activities of RXR agonists.

1. Lessons from Knockout Mice

RXR is an obligatory partner for many nuclear receptors important during development (Mangelsdorf and Evans, 1995). Thus, its constitutive deletion likely affects a very diverse array of developmental and physiological pathways. This has been clearly underlined by the thorough phenotypic analyses of the developmental defects occurring in mice carrying various RXR gene deletions or mutations. Whereas RXRfi and RXRg null mutations give rise to rather minor developmental defects, RXRa null mice die at early embryonic stages (Kastner et al., 1994; Sucov et al., 1994). This lethality might be due to defects in the PPARb- and PPARg-signaling pathways, since the invalidation of any of these genes leads to embryonic lethality with placental defects that are timely overlapping with those observed in RXRa null placenta (Barak et al., 1999; Nadra et al., 2006; Wendling et al., 1999). Other defects analyzed in the various RXR mutants are seen in various tissues, such as the skin, the eye, the heart, and the testis, and reflect alterations in the pathways of other receptors. While RARs, which transduce the vitamin A activities through the RA signal, play a major role, TR- and VDR-dependent pathways are also affected (Mark et al., 1999; Wendling et al., 1999; reviewed in Mark et al., 2006).

From the metabolic point of view, analyzing the importance of RXRa in "metabolic" adult tissues required the generation of tissue-specific knockouts. Specific invalidation of RXRa has been generated in liver, and metabolic studies were performed to identify which pathways were most affected. As could be expected, many PPARa-mediated functions in fatty acid oxidation were altered due to the lack of RXRa. However, other pathways that include LXR and FXR pathways were also compromised, at least partially, by the absence of RXRa. These effects could not be compensated for by RXRb and RXRg (Imai et al, 2001b; Wan et al, 2000a,b). Invalidation of RXRa in the adipose tissue of adult animals resulted in an alteration of preadipocyte differentiation as well as in resistance to induced obesity (Imai et al., 2001a). These results are reminiscent of the observations obtained with PPARg heterozygous mice (Kubota et al., 1999) and with an adipose-specific deletion of PPARg (Imai et al., 2004a), suggesting that most of the effects due to the lack of RXRa expression reflect altered PPARg functions (Imai et al., 2001a). However, the impaired lipolysis observed in these mice might be related to an alteration of LXR:RXR heterodimer signaling.

2. The Pharmacological Activity of RXR Agonists

As mentioned above, RXR is a bona fide receptor but the nature of its endogenous ligand, if any, remains elusive. Thus, all observations made so far were obtained in a pharmacological context, treating mice with 9-cis RA or synthetic RXR agonists. On such treatments, RXR may regulate transcription as a homodimer (RXR:RXR), binding to DR-1 like response elements. However, most of RXR agonist activities likely rely on the activation of permissive heterodimers, raising a major interest in the exploitation of this ability for therapeutic purposes.

The first application of rexinoids in clinical studies took advantage of their efficacy in triggering apoptosis, in contrast to cell differentiation seen with retinoids (Mehta et al., 1996; Nagy et al., 1995). This led to their successful use since the 1980s in the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Presently, a number of cancer types and cell types are being tested for their possible responsiveness to rexinoids, such as acute myeloid leukemia (Altucci et al., 2005), aerodigestive tract cancer (Dragnev et al., 2005), human breast cancer cells (Toma et al., 1998), or pancreatic cancer cells (Balasubramanian et al., 2004). Along the same line, chemopreventive n-3 fatty acids in colon were shown to activate RXR in colonocytes (Fan et al., 2003).

However, initial studies as well as phase 2 and 3 clinical trials with bexar-otene (Targretin® capsules corresponding to the well-characterized rexinoid LG1069) reported high triglyceridemia, hypothyroidism, and hypercholester-olemia (Duvic et al., 2001; Rizvi et al., 1999). In parallel, global gene expression profiles of various tissues from rats treated with bexarotene further underscore its action on metabolic pathways (Wang et al., 2006).

Actually, numerous studies have reported the broad impact of RXR synthetic ligands on metabolic regulations in the adult organism. The first seminal observation was that in vivo administration of the synthetic specific RXR ligands mimics—and increases when given in combination with TZD—the metabolic effects of PPARg ligands, by decreasing hyperglycemia, and improving insulin sensitivity (Mukherjee et al., 1997, 1998).

The crucial role of muscle physiology in insulin sensitivity oriented the search for the mechanism on this tissue, where rexinoids were shown to activate a number of genes related to fatty acid uptake (CD36) and desaturation (SCD1), while increasing glycogen synthase activity in muscle cells in culture and improving glucose disposal in skeletal muscles (Cha et al., 2001; Shen et al., 2004; Singh Ahuja et al., 2001; reviewed in Szanto et al., 2004b). Because PPARg agonists are also insulin sensitizer, the first hypothesis was that PPARg is the partner of RXR in these rexinoid activities. However, careful and extensive gene expression analyses comparing TZD and rexi-noids activities revealed some common but also some clearly distinct target genes and tissue-specific activities. More particularly, rexinoids act primarily in the liver and the skeletal muscle, in contrast to TZD which exert their effects mainly on the adipose tissue and to a lesser extent in muscle (Shen et al., 2004; Singh Ahuja et al., 2001). Thus, PPARa, PPARb, and LXR must be considered as likely partners accounting for rexinoid action, since all were found to have some antidiabetic activity (Cao et al., 2003; Lee et al., 2006; Park et al., 2006). In addition, the regulation of many genes by rexinoids in the liver was also PPARa dependent (Ouamrane et al., 2003).

With respect to lipid metabolism, rexinoids provoke a very efficient inhibition of cholesterol absorption. A dual mechanism for this is proposed: repression of bile acid production via inhibition of Cyp7A in an FXR-dependent manner and increased efflux of cholesterol from enterocytes into the lumen via an LXR:RXR-dependent induced expression of the transport protein ABC1 (Repa et al., 2000b). Positive effects are also observed in the apoE^~ mouse model where rexinoids reduced the development of atherosclerosis (Claudel et al., 2001), likely through the concomitant activation of PPAR- and LXR-signaling pathways in macrophages (Szanto et al., 2004a).

Paradoxically, rexinoids may also antagonize FXR activity, an effect which may result from the disruption of the ability of the FXR:RXR heter-odimer to interact with coactivators, as seen on the BSEP promoter (Kassam et al., 2003). Another paradoxical effect concerns a severe hypertriglyceride-mia frequently observed in human and in some animal models (Miller et al., 1997). It has been linked to reduced LPL activity in skeletal and cardiac tissue (Davies et al., 2001), but the nature of corresponding heterodimer involved is elusive, as neither PPARs, nor LXR or RAR may explain this effect. Also unexpectedly, rexinoid treatment provokes a central hypothy-roidism, due to the specific inhibition of TSH expression and secretion (Liu et al., 2002; Sharma et al., 2006), and which may explain some cases of rexinoid-associated hypercholesterolemia.

These observations underline the problem that faces the experimentalist with such a promiscuous agent. On the one hand, it is difficult to predict the scope of changes that a specific RXR ligand may provoke in the whole organism with respect to metabolic homeostasis. On the other hand, the pleiotropic action of RXR might also be an advantage in the context of complex and multifactorial diseases, still raising interest in the identification of RXR ligands specific for a given or a limited number of heterodimers, allowing more targeted therapeutic approaches of metabolic diseases. In that respect, new agonists but also antagonists are proposed (Cavasotto et al., 2004; Cesario et al., 2001; Deng et al., 2005). In parallel, intensive screening for RXR modulators are performed (Gernert et al., 2003,2004; Haffner et al., 2004), more particularly searching for molecules active on type 2 diabetes (Leibowitz et al., 2006; Michellys et al., 2003a,b).

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