LXRs, Liver X receptors

Another receptor, LXR (Liver X receptor), also exists in alpha and beta forms, and acts as a receptor for cholesterol and its degradation products, which accumulate when cholesterol levels are high. LXRs are expressed in the liver and lower digestive tract, where they regulate cholesterol and bile-acid homeostasis. LXR-beta activates reverse cholesterol transport from the periphery to the liver. LXR-alpha, which is found in the liver, promotes catabolism in the liver and drives catabolism of cholesterol to BAs. Its activation in the liver increases... 

Abbreviations. AhR, aromatic hydrocarbon receptor TCDD, tetrachlorodibenzodioxin PXR, pregnenolone-16a-nitrile-X-receptor PCN, pregnenolone-16a-nitrile CAR, constitutive androstane receptor MC, methylcholanthrene PPARa, peroxisome proliferated-activated receptor-a FXR, famesoid-X-receptor LXR, liver-X-receptor RXR, retinod-X-receptor 5-HETE, 5-OH-eicosatetraenoic acid LTB4, leukotriene B4 13-HODE, hydroxyoctadecadienoic acid DMXAA, dimethylxan-thenone-4-acetic acid. 

The area of HDL cholesterol metabolism and function holds considerable promise in atheroprotection. Novel HDL-directed therapeutic interventions mainly target LXR (liver X receptor), ABCA1, apoA-I, CEPT (cholesteryl ester transfer protein), and EL (endothelial lipase) [12, 16, 70], The contribution of pharmacogenomics in the development of such drugs has not only been proven to be important (Fig. 2) but been required by the international drug regulatory bodies. Representative examples are presented below. 

EMERGING ROLE OF RETINOID-RELATED ORPHAN RECEPTOR (ROR) AND ITS CROSS TALK WITH LXR (LIVER X RECEPTOR) IN THE REGULATION OF DRUG-METABOLIZING ENZYMES... 

For example, hepatocytes express LXR (liver X receptor), a nuclear receptor that senses the levels of oxysterols. When cellular cholesterol Increases in the liver, oxysterols are generated and activate LXR. Activated LXR stimulates the expression of cholesterol 7ct-hydroxylase, the key rate-limiting enzyme In the hepatic conversion of cholesterol Into bile acids, a major pathway for disposing of excess cholesterol from the body. LXR also stimulates the expression of the ABC proteins that export cholesterol Into the bile (ABCG5/8) or onto lipoproteins in the blood (ABCAl). In... 

Abbreviations a-BFAs anteiso-branched fatty acids AGP acyl carrier protein BHLH active soluble domain of SREBP CNS central nervous system DSD delta 5 desaturase D6D delta 6 desaturase ER endoplasmic reticulum Hik histidine kinase HUFA highly unsaturated fatty acid LXR liver X receptor MUFA monounsaturated fatty add NF-Y nuclear factor Y PLs phospholipids PP peroxisome proliferator PPAR PP-activated receptor PPRE PP response element PUFA polyunsaturated fatty acid PUFA-BP PUFA binding protein PUFA-RE PUFA response element RXR retinoid X receptor SCAP SREBP cleavage-activating protein SCD steraroyl CoA desaturase SFA saturated fatty acid SRE sterol response... 

Fig. 6. Coordinated transcriptional regulation of fatty acid desaturases and elongases in mammals. PUFA, polyunsaturated fatty acids +, stimulation inhibition LXR, liver X receptor RXR retinoid X receptor SREBP, sterol regulatory element binding protein ChREBP, carbohydrate response element binding protein Mix, Max-like receptor PPAR-ot, peroxisome proliferator activated receptor alpha LXRE, liver X receptor response element SRE, sterol response element ChoRE, carbohydrate response element PPRE, peroxisome proliferator response element. (See color plate section, plate no. 6.)...

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