Circulation. 2002;106:1147-1153
Published online before print August 5, 2002, doi: 10.1161/01.CIR.0000026802.79202.96
Published online before print August 5, 2002, doi: 10.1161/01.CIR.0000026802.79202.96
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;106:1147.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Accumulation of Foam Cells in Liver X Receptor-Deficient Mice
From the Department of Biosciences at Novum, Karolinska Institutet (G.U.S., P.P., L.W., S.A., K.R.S., B.A., J.G.), Huddinge, Sweden; Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine, Karolinska Institutet at Huddinge University Hospital (P.P., B.A.), Stockholm, Sweden; and Center for Molecular Medicine, Karolinska Institutet at Karolinska Hospital (G.K.H.), Stockholm, Sweden. Dr Alberti is now at the University of Tübingen, Institute for Cell Biology, Department of Molecular Biology, Tübingen, Germany.
Correspondence to Gertrud Schuster, Karolinska Institutet, Center for Biotechnology at Novum, S-141 57 Huddinge, Sweden. E-mail gertrud.schuster{at}csb.ki.se
Background— The nature of some of the target genes for liver X receptors (LXRs)-
and -ß, such as sterol regulatory element binding protein-1 and ATP-binding cassette transporter proteins, suggests a pivotal role of these nuclear receptors in the regulation of fatty acid and cholesterol homeostasis. The present study aimed to elucidate the physiological relevance of both LXRs with regard to lipid metabolism and macrophage cholesterol efflux.
Methods and Results— Mice depleted for LXR, LXRß, or both were fed low-fat rodent chow for 18 months before investigations. The combined deficiency of LXR and LXRß was linked to impaired triglyceride metabolism, increased LDL and reduced HDL cholesterol levels, and cholesterol accumulation in macrophages (foam cells) of the spleen, lung, and arterial wall.
Conclusions— Our data demonstrate the physiological importance of both LXRs in lipid metabolism and strongly indicate that both LXRs have a protective role against the development of atherosclerosis.
Key Words: receptors, liver X • atherosclerosis • lipoproteins • fatty acids • cholesterol
This article has been cited by other articles:
 |
|
 |
|
  F. Lalloyer, T. A. Pedersen, B. Gross, S. Lestavel, S. Yous, E. Vallez, J.-A. Gustafsson, S. Mandrup, C. Fievet, B. Staels, et al. Rexinoid Bexarotene Modulates Triglyceride but not Cholesterol Metabolism via Gene-Specific Permissivity of the RXR/LXR Heterodimer in the Liver Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1488 - 1495. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.-L. Vedin, S. A. Lewandowski, P. Parini, J.-A. Gustafsson, and K. R. Steffensen The oxysterol receptor LXR inhibits proliferation of human breast cancer cells Carcinogenesis, April 1, 2009; 30(4): 575 - 579. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Bjorkhem Are side-chain oxidized oxysterols regulators also in vivo? J. Lipid Res., April 1, 2009; 50(Supplement): S213 - S218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Gabbi, M. Warner, and J.-A. Gustafsson Minireview: Liver X Receptor {beta}: Emerging Roles in Physiology and Diseases Mol. Endocrinol., February 1, 2009; 23(2): 129 - 136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-J. Kim, L. C. Andersson, D. Bouton, M. Warner, and J.-A. Gustafsson Stromal growth and epithelial cell proliferation in ventral prostates of liver X receptor knockout mice PNAS, January 13, 2009; 106(2): 558 - 563. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. E. van Straten, N. C. A. Huijkman, J. F. W. Baller, F. Kuipers, and T. Plosch Pharmacological activation of LXR in utero directly influences ABC transporter expression and function in mice but does not affect adult cholesterol metabolism Am J Physiol Endocrinol Metab, December 1, 2008; 295(6): E1341 - E1348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Teupser, D. Kretzschmar, C. Tennert, R. Burkhardt, W. Wilfert, D. Fengler, R. Naumann, A. E. Sippel, and J. Thiery Effect of Macrophage Overexpression of Murine Liver X Receptor-{alpha} (LXR-{alpha}) on Atherosclerosis in LDL-Receptor Deficient Mice Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 2009 - 2015. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Zanotti, F. Poti, M. Pedrelli, E. Favari, E. Moleri, G. Franceschini, L. Calabresi, and F. Bernini The LXR agonist T0901317 promotes the reverse cholesterol transport from macrophages by increasing plasma efflux potential J. Lipid Res., May 1, 2008; 49(5): 954 - 960. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. P. Torra, N. Ismaili, J. E. Feig, C.-F. Xu, C. Cavasotto, R. Pancratov, I. Rogatsky, T. A. Neubert, E. A. Fisher, and M. J. Garabedian Phosphorylation of Liver X Receptor {alpha} Selectively Regulates Target Gene Expression in Macrophages Mol. Cell. Biol., April 15, 2008; 28(8): 2626 - 2636. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Smoak, J. Madenspacher, S. Jeyaseelan, B. Williams, D. Dixon, K. R. Poch, J. A. Nick, G. S. Worthen, and M. B. Fessler Effects of Liver X Receptor Agonist Treatment on Pulmonary Inflammation and Host Defense J. Immunol., March 1, 2008; 180(5): 3305 - 3312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Commerford, L. Vargas, S. E. Dorfman, N. Mitro, E. C. Rocheford, P. A. Mak, X. Li, P. Kennedy, T. L. Mullarkey, and E. Saez Dissection of the Insulin-Sensitizing Effect of Liver X Receptor Ligands Mol. Endocrinol., December 1, 2007; 21(12): 3002 - 3012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Zelcer, N. Khanlou, R. Clare, Q. Jiang, E. G. Reed-Geaghan, G. E. Landreth, H. V. Vinters, and P. Tontonoz Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors PNAS, June 19, 2007; 104(25): 10601 - 10606. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. D. Moore, S. Kato, W. Xie, D. J. Mangelsdorf, D. R. Schmidt, R. Xiao, and S. A. Kliewer International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor {alpha}, Farnesoid X Receptor beta, Liver X Receptor {alpha}, Liver X Receptor beta, and Vitamin D Receptor Pharmacol. Rev., December 1, 2006; 58(4): 742 - 759. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Quinet, D. A. Savio, A. R. Halpern, L. Chen, G. U. Schuster, J.-A. Gustafsson, M. D. Basso, and P. Nambi Liver X Receptor (LXR)-beta Regulation in LXR{alpha}-Deficient Mice: Implications for Therapeutic Targeting Mol. Pharmacol., October 1, 2006; 70(4): 1340 - 1349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang, X. Zhang, L. Chen, J. Wu, D. Su, W. J. Lu, M.-T. Hwang, G. Yang, S. Li, M. Wei, et al. Liver X receptor agonist TO-901317 upregulates SCD1 expression in renal proximal straight tubule Am J Physiol Renal Physiol, May 1, 2006; 290(5): F1065 - F1073. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Gnerre, G. U. Schuster, A. Roth, C. Handschin, L. Johansson, R. Looser, P. Parini, M. Podvinec, K. Robertsson, J.-A. Gustafsson, et al. LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver J. Lipid Res., August 1, 2005; 46(8): 1633 - 1642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Johansson, M. Rudling, T. S. Scanlan, T. Lundasen, P. Webb, J. Baxter, B. Angelin, and P. Parini Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice PNAS, July 19, 2005; 102(29): 10297 - 10302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Gerin, V. W. Dolinsky, J. G. Shackman, R. T. Kennedy, S.-H. Chiang, C. F. Burant, K. R. Steffensen, J.-A. Gustafsson, and O. A. MacDougald LXR{beta} Is Required for Adipocyte Growth, Glucose Homeostasis, and {beta} Cell Function J. Biol. Chem., June 17, 2005; 280(24): 23024 - 23031. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Papadopoulos Cholesterol Homeostasis and Infertility: The Liver X Receptor Connection Endocrinology, June 1, 2005; 146(6): 2517 - 2518. [Full Text] [PDF]
|
|
|
|
|
|
K. M. Robertson, G. U. Schuster, K. R. Steffensen, O. Hovatta, S. Meaney, K. Hultenby, L. C. Johansson, K. Svechnikov, O. Soder, and J.-A. Gustafsson The Liver X Receptor-{beta} Is Essential for Maintaining Cholesterol Homeostasis in the Testis Endocrinology, June 1, 2005; 146(6): 2519 - 2530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. N. Bradley and P. Tontonoz Lesion Macrophages Are a Key Target for the Antiatherogenic Effects of LXR Agonists Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 10 - 11. [Full Text] [PDF]
|
|
|
|
|
|
N. Levin, E. D. Bischoff, C. L. Daige, D. Thomas, C. T. Vu, R. A. Heyman, R. K. Tangirala, and I. G. Schulman Macrophage Liver X Receptor Is Required for Antiatherogenic Activity of LXR Agonists Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 135 - 142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. R Steffensen, S. Y. Neo, T. M Stulnig, V. B Vega, S. S Rahman, G. U Schuster, J.-A. Gustafsson, and E. T Liu Genome-wide expression profiling; a panel of mouse tissues discloses novel biological functions of liver X receptors in adrenals J. Mol. Endocrinol., December 1, 2004; 33(3): 609 - 622. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Ulven, K. T. Dalen, J.-A. Gustafsson, and H. I. Nebb Tissue-specific autoregulation of the LXR{alpha} gene facilitates induction of apoE in mouse adipose tissue J. Lipid Res., November 1, 2004; 45(11): 2052 - 2062. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wu, Y. Zhang, N. Wang, L. Davis, G. Yang, X. Wang, Y. Zhu, M. D. Breyer, and Y. Guan Liver X receptor-{alpha} mediates cholesterol efflux in glomerular mesangial cells Am J Physiol Renal Physiol, November 1, 2004; 287(5): F886 - F895. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ando, S. Tsuruoka, H. Yamamoto, T. Takamura, S. Kaneko, and A. Fujimura Effects of Pravastatin on the Expression of ATP-Binding Cassette Transporter A1 J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 420 - 425. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. R. Steffensen and J.-A. Gustafsson Putative Metabolic Effects of the Liver X Receptor (LXR) Diabetes, February 1, 2004; 53(90001): S36 - 42. [Abstract] [Full Text]
|
|
|
|
|
|
K. T. Dalen, S. M. Ulven, K. Bamberg, J.-A. Gustafsson, and H. I. Nebb Expression of the Insulin-responsive Glucose Transporter GLUT4 in Adipocytes Is Dependent on Liver X Receptor {alpha} J. Biol. Chem., November 28, 2003; 278(48): 48283 - 48291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Farnegardh, T. Bonn, S. Sun, J. Ljunggren, H. Ahola, A. Wilhelmsson, J.-A. Gustafsson, and M. Carlquist The Three-dimensional Structure of the Liver X Receptor {beta} Reveals a Flexible Ligand-binding Pocket That Can Accommodate Fundamentally Different Ligands J. Biol. Chem., October 3, 2003; 278(40): 38821 - 38828. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. G. Lund, J. G. Menke, and C. P. Sparrow Liver X Receptor Agonists as Potential Therapeutic Agents for Dyslipidemia and Atherosclerosis Arterioscler Thromb Vasc Biol, July 1, 2003; 23(7): 1169 - 1177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Tontonoz and D. J. Mangelsdorf Liver X Receptor Signaling Pathways in Cardiovascular Disease Mol. Endocrinol., June 1, 2003; 17(6): 985 - 993. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Castrillo, S. B. Joseph, C. Marathe, D. J. Mangelsdorf, and P. Tontonoz Liver X Receptor-dependent Repression of Matrix Metalloproteinase-9 Expression in Macrophages J. Biol. Chem., March 14, 2003; 278(12): 10443 - 10449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. K. Juvet, S. M. Andresen, G. U. Schuster, K. T. Dalen, K. A. R. Tobin, K. Hollung, F. Haugen, S. Jacinto, S. M. Ulven, K. Bamberg, et al. On the Role of Liver X Receptors in Lipid Accumulation in Adipocytes Mol. Endocrinol., February 1, 2003; 17(2): 172 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Stulnig, K. R. Steffensen, H. Gao, M. Reimers, K. Dahlman-Wright, G. U. Schuster, and J.-A. Gustafsson Novel Roles of Liver X Receptors Exposed by Gene Expression Profiling in Liver and Adipose Tissue Mol. Pharmacol., December 1, 2002; 62(6): 1299 - 1305. [Abstract] [Full Text] [PDF]
|
|