Liver X Receptors (LXR) as Therapeutic Targets in Dyslipidemia

被引:110
作者
Beltowski, Jerzy [1 ]
机构
[1] Med Univ, Dept Pathophysiol, PL-20090 Lublin, Poland
关键词
Atherosclerosis; Lipogenesis; Liver X receptor; Oxysterols; Reverse cholesterol transport;
D O I
10.1111/j.1755-5922.2008.00062.x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Liver X receptors (LXR) alpha and beta belong to a family of nuclear receptors which form heterodimers with the retinoid X receptor (RXR) and, upon ligand binding, stimulate the expression of target genes. LXR were initially described as orphan receptors and later oxidized cholesterol derivatives (oxysterols) were identified as their natural ligands. In addition, several synthetic LXR agonists such as T0901317 and GW3965 were synthesized. Oxysterols are formed in amounts proportional to cholesterol content in the cell and therefore LXR operate as cholesterol sensors which protect from cholesterol overload by inhibiting intestinal cholesterol absorption, stimulating cholesterol efflux from cells to high-density lipoproteins (HDL), its transport to the liver, conversion to bile acids, and biliary excretion. In addition, LXR agonists activate fatty acid synthesis by stimulating the expression of a lipogenic transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c), leading to the elevation of plasma triglycerides and liver steatosis. Lipogenic effect seems is the most important negative feature of LXR agonists considered as potential hypolidemic drugs. Some of currently used drugs also affect LXR signaling. For example, statins may impair LXR signaling by inhibiting oxysterol synthesis, whereas fibrates and thiazolidinediones increase LXR expression and activity.
引用
收藏
页码:297 / 316
页数:20
相关论文
共 136 条
[1]   Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRβ-deficient mice [J].
Alberti, S ;
Schuster, G ;
Parini, P ;
Feltkamp, D ;
Diczfalusy, U ;
Rudling, M ;
Angelin, B ;
Björkhem, I ;
Pettersson, S ;
Gustafsson, JÅ .
JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (05) :565-573
[2]   Effects of pravastatin on the expression of ATP-binding cassette transporter A1 [J].
Ando, H ;
Tsuruoka, S ;
Yamamoto, H ;
Takamura, T ;
Kaneko, S ;
Fujimura, A .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2004, 311 (01) :420-425
[3]   Fenofibric acid, an active form of fenofibrate, increases apolipoprotein A-I-mediated high-density lipoprotein biogenesis by enhancing transcription of ATP-binding cassette transporter A1 gene in a liver X receptor-dependent manner [J].
Arakawa, R ;
Tamehiro, N ;
Nishimaki-Mogami, T ;
Ueda, K ;
Yokoyama, S .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2005, 25 (06) :1193-1197
[4]   Assessing the effects of LXR agonists on cellular cholesterol handling: a stable isotope tracer study [J].
Aravindhan, Karpagam ;
Webb, Christine L. ;
Jaye, Michael ;
Ghosh, Avijit ;
Willette, Robert N. ;
DiNardo, N. John ;
Jucker, Beat M. .
JOURNAL OF LIPID RESEARCH, 2006, 47 (06) :1250-1260
[5]   Regulation of macrophage cholesterol efflux through hydroxymethylglutaryl-CoA reductase inhibition [J].
Argmann, CA ;
Edwards, JY ;
Sawyez, CG ;
O'Neil, CH ;
Hegele, RA ;
Pickering, JG ;
Huff, MW .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (23) :22212-22221
[6]   Selective up-regulation of LXR-regulated genes ABCA1, ABCG1, and APOE in macrophages through increased endogenous synthesis of 24(S),25-epoxycholesterol [J].
Beyea, Michael M. ;
Heslop, Claire L. ;
Sawyez, Cynthia G. ;
Edwards, Jane Y. ;
Markle, Janet G. ;
Hegele, Robert A. ;
Huff, Murray W. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (08) :5207-5216
[7]   Coadministration of a liver X receptor agonist and a peroxisome proliferator activator receptor-α agonist in mice:: Effects of nuclear receptor interplay on high-density lipoprotein and triglyceride metabolism in vivo [J].
Beyer, TP ;
Schmidt, RJ ;
Foxworthy, P ;
Zhang, YY ;
Dai, JN ;
Bensch, WR ;
Kauffman, RF ;
Gao, H ;
Ryan, TP ;
Jiang, XC ;
Karathanasis, SK ;
Eacho, PI ;
Cao, GQ .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2004, 309 (03) :861-868
[8]   24(S),25-epoxycholesterol - A potential friend [J].
Bjorkhem, I ;
Diczfalusy, U .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2004, 24 (12) :2209-2210
[9]   ATHEROSCLEROSIS AND STEROL 27-HYDROXYLASE - EVIDENCE FOR A ROLE OF THIS ENZYME IN ELIMINATION OF CHOLESTEROL FROM HUMAN MACROPHAGES [J].
BJORKHEM, I ;
ANDERSSON, O ;
DICZFALUSY, U ;
SEVASTIK, B ;
XIU, RJ ;
DUAN, CG ;
LUND, E .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (18) :8592-8596
[10]   Importance of a novel oxidative mechanism for elimination of brain cholesterol - Turnover of cholesterol and 24(S)-hydroxycholesterol in rat brain as measured with O-18(2) techniques in vivo and in vitro [J].
Bjorkhem, I ;
Lutjohann, D ;
Breuer, O ;
Sakinis, A ;
Wennmalm, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (48) :30178-30184