LXR

From LipidomicsWiki

LIVER X RECEPTORS, THE STEROL SENSORS
In addition to its expression in the liver, LXR is also abundantly expressed in other tissues associated with lipid metabolism, including adipose, kidney, intestine, lung, adrenals, and macrophages, whereas LXR is ubiquitously expressed (Lu et al. 2001). The LXRs are activated by naturally occurring oxysterols including 24(S)-hydroxycholesterol (brain), 22(R)- hydroxycholesterol (adrenal), 24(S),25-epoxycholesterol (liver), and 27-hydroxycholesterol (human macrophage) (Lu et al. 2001; Fu et al. 2001). Evidence also suggests that LXR activation can be antagonized by other small lipophilic agents, including 22(S)- hydroxycholesterol, certain unsaturated fatty acids, and geranylgeranyl pyrophosphate
(Spencer et al. 2001; Ou et al. 2001). LXRs act as cholesterol sensors that respond to elevated sterol concentrations, and transactivate a cadre of genes that govern transport, catabolism, and elimination of cholesterol (Lu et al. 2001). LXRs also regulate a number of genes involved in fatty acid metabolism (Repa et al. 2000; Schultz et al. 2000). In the LXR metabolic cascade, several sterol transporters have been identified as targets, including ABCA1, ABCG1, ABCG4, ABCG5, and ABCG8 Repa et al. 2000; Costet et al. 2000; Venkateswaran et al. 2000; Engel et al. 2001; Berge et al. 2000). ABCA1 is a monomeric transporter that resides in the plasma membrane of tissues, including liver, intestine, placenta, adipose, and spleen. ABCA1 transports phospholipids and cholesterol and is believed to be the rate-limiting step in reverse cholesterol transport ( Tall and Wang 2000). The dimeric transporters ABCG1, ABCG4, ABCG5, and ABCG8, are likely to be associated with membranes of intracellular organelles and have allbeen implicated in the intracellular trafficking of sterols in macrophages (for ABCG1 and perhaps ABCG4), and in liver and small intestine (for ABCG5 and ABCG8). Mutations in the genes for ABCA1 and ABCG5/G8 result in two disorders in cholesterol metabolism: Tangier disease and sitosterolemia (Berge et al. 2000, Tall and Wang 2000). These genes therefore play pivotal roles in the cellular flux of lipids from macrophages, and the biliary secretion and intestinal absorption of sterols. No cytosolic binding proteins have yet been identified as target genes of the LXRs, although one or more of the newly described oxysterol-binding proteins may fulfill such a role. However, in rodents, the CYP enzyme cholesterol 7 -hydroxylase (CYP7A1) has been shown to be an important LXR target gene. CYP7A1 encodes the rate-limiting enzyme in the neutral bile acid biosynthetic pathway and is one of the principle means for eliminating cholesterol from the body. Mice lacking LXR fail to increase production of CYP7A1 and exhibit profound liver
accumulation of cholesterol esters (Peet et al. 1998). Mice lacking only LXR do not exhibit this alteration in bile acid metabolism, suggesting that the two LXRs may subserve distinct biological roles (Alberti et al. 2001). The human LXR gene is itself a target of the LXR signaling pathway (Whitney et al. 2001; Lafitte et al. 2001). Particularly in macrophages, the autoregulation of LXR would be an important way to amplify the cholesterol catabolic cascade.