“Don't Know Much Bile-ology”

The work discussed above and an additional paper strengthen the notion that nuclear receptors are key regulators of cholesterol catabolism. The paper by Repa et al. links RXRs and LXRs to pathways of cholesterol absorption and efflux (Repa et al. 2000xRepa, J.J, Turley, S.D, Lobaccaro, J.A, Medina, J, Li, L, Lustig, K, Shan, B, Heyman, R.A, Dietschy, J.M, and Mangelsdorf, D.J. Science. 2000; 289: 1524–1529Crossref | PubMed | Scopus (953)See all ReferencesRepa et al. 2000). These authors found that treatment of mice with the RXR ligand, LG268, results in potent inhibition of cholesterol absorption. A decrease in bile acid pool size and an induction of ABCA1, an ABC family transporter that mediates cholesterol efflux from cells, are each partly responsible for decreased cholesterol absorption. Furthermore, the LXR/RXR heterodimer specifically regulates the expression of ABCA1, since neither LG268 nor T0901317 (an LXR-specific agonist) can induce ABCA1 in LXRα/β double knockout mice. This body of work implicates nuclear receptors as the key regulators for cholesterol catabolism and efflux, and suggests that the cross talk between nuclear receptors may serve to regulate pathways of cholesterol and lipid homeostasis (Figure 1Figure 1).In the past few years, the perception of nuclear receptors as ligand-modulated transcription factors whose primary role is to mediate the effects of endocrine signals has been altered by the discovery of a multitude of orphan receptors that can respond to dietary components, products of intermediary metabolism, and xenobiotic chemicals (Blumberg and Evans 1998xBlumberg, B and Evans, R.M. Genes Dev. 1998; 12: 3149–3155Crossref | PubMedSee all ReferencesBlumberg and Evans 1998). The present work delineates the genetic hierarchy that regulates cholesterol and bile acid homeostasis: LXR α/β govern the uptake of dietary cholesterol by controlling its intestinal transporter, and the interactions among FXR, SHP, and LRH-1 form the basis for the coordinated regulation of cholesterol degradation and bile acid secretion. In macrophages and perhaps other tissues, expression of PPARγ, a target of known prescription drugs, establishes an additional layer of regulation of cholesterol efflux and absorption while RXR participates at all sites as a partner of PPARγ, LXR α/β, and FXR.As a complement to traditional cholesterol-lowering drugs that focus on inhibition of endogenous synthesis, the identification of this collection of nuclear receptors that mediates cholesterol absorption, reverse transport, and degradation provides an unprecedented opportunity to pharmacologically manipulate these natural cholesterol-controlling pathways. Each is a potentially interesting drug development target. RXR compounds have been shown to be effective insulin sensitizers as well as potent inhibitors of cholesterol absorption and bile acid synthesis in animals (Mukherjee et al. 1997xMukherjee, R, Davies, P.J, Crombie, D.L, Bischoff, E.D, Cesario, R.M, Jow, L, Hamann, L.G, Boehm, M.F, Mondon, C.E, Nadzan, A.M et al. Nature. 1997; 386: 407–410Crossref | PubMed | Scopus (495)See all ReferencesMukherjee et al. 1997). PPARγ ligands are already widely used in treatment of type II diabetes and more recently show promise in animals as inhibitors of atherosclerosis (Willson et al. 2000xWillson, T.M, Brown, P.J, Sternbach, D.D, and Henke, B.R. J. Med. Chem. 2000; 43: 527–550Crossref | PubMed | Scopus (1433)See all ReferencesWillson et al. 2000). Synthetic LXR agonists may lower serum cholesterol levels by decreasing intestinal absorption while preventing hepatic accumulation. FXR activators may be useful to treat disorders of bile acid metabolism. Although not yet identified, small molecules that regulate SHP and LRH-1 could be useful in cases of either hypercholesterolemia or cholestasis, though certainly much less is understood regarding the extent and specificity of their regulation. In spite of the tinkering that may be necessary to develop clinical weapons based on our new knowledge, the fact that at least six nuclear receptors regulate distinct aspects of cholesterol homeostasis means that new drugs controlling their activity will be discovered.*To whom correspondence should be addressed (e-mail: evans@salk.edu).