SHAPE Society

1. Editorial Slides
VP Watch, January 22, 2003, Volume 3, Issue 3
Does LXR Links Lipid Metabolism to
Inflammation, or PPAR?

2.  The Liver X receptors
(LXRs) are members of the
nuclear receptor superfamily
activated by oxysterols and
play an important role in
maintaining lipid and
lipoprotein homeostasis.

3.  In macrophages, where both
LXRs are highly expressed,
these receptors control the
cholesterol efflux pathway
through the regulation of
target genes including
ABCA1 and apolipoprotein E.

4. The synthetic LXR ligand GW3965
reduces the development of
atherosclerosis in LDL receptor and
apoE deficient mice. (2).
 Conversely, LXRab null mice
exhibit foam cell accumulation in
multiple tissues, including aorta,
lung, spleen and brain (2).

5.  Transplantation of LXR deficient
bone marrow into LDLR and
apoE knockout mice resulted in
increased atherosclerosis,
demonstrating the relevance of
macrophage LXR activity in the
prevention of atherosclerosis (1).

6. MMP-9 is highly expressed by
macrophages and smooth
muscle cells in areas of
atheroma formation and
participates in the degradation of
ECM components at the shoulder
regions of atherosclerotic lesions.

7. As highlighted in VP Watch of
this week, Castrillo et al. have
shown that ligand activation of
LXRs in macrophages inhibits
both basal and cytokine
inducible expression of the
MMP-9 gene.(1)

8.  The results of this study
demonstrate that LXRa and
LXRb are negative regulators
of MMP-9 expression in
macrophages, and are
consistent with recent
observations that LXR agonists
repress the expression of
multiple NF-kB target genes.

9.  The LXR-selective agonists
GW3965 and T1317 inhibit
MMP-9 expression induced by
LPS, TNFa and IL-1b,
suggesting that they are likely
to act on common downstream
effectors of these signaling
pathways.

10. The American Society for Biochemistry and Molecular Biology
From JBC January 16, 2003 (1)

11. The American Society for Biochemistry and Molecular Biology.
From JBC January 16, 2003 (1)

12.  Interestingly, other members of
the nuclear receptor family,
including PPAR (proxisome
proliferator activated receptor)
and GR (glucocorticoid
receptor), have also been shown
to inhibit MMP-9 expression.

13.  Administration of synthetic PPAR
gamma ligands to apoE -/- mice
decreases the expression of MMP-9
in aortic tissue (4).
 In vitro, high concentrations of
rosiglitazone (PPAR gamma ligand)
inhibit macrophage activation,
including MMP-9 expression (5).

14. Conclusion:
 LXR (LXRa and LXRb) and PPAR
are negative regulators of MMP-9
expression in macrophages.
 They are involved in lipid and
glucose metabolism.
 Also, they interfere with NFKappa
B signaling patway.

15. Conclusion:
 Therefore, LXR and PPAR both
are important players in the chain
of atherosclerosis, linking
between lipid metabolism, insulin
resistance, and inflammatory
process contributing in plaque
formation and its rupture.

16. Question:
 Since the suppressive effect of PPAR gamma
ligands on MMP-9 is also observed in PPAR
gamma deficient -/- cells, the question is:
What is the mechanism through
which PPAR gamma reduce MMP-9,
and whether LXR ligands would have
similar suppressive effect on MMP-9
in LXR deficient cells?

17. Conclusion:
 Does LXR agonist,
GW3965, presents a likely
candidate for stabilization
of vulnerable plaque?

18. ReferencesReferences
1- Antonio Castrillo, Sean B. Joseph, Chaitra Marathe, David J.
Mangelsdorf, Peter Tontonoz
JBC Papers in Press. Published on January 16, 2003 as Manuscript
M213071200
2- Laffitte, B. A., Repa, J. J., Joseph, S. B., Wilpitz, D. C., Kast, H. R.,
Mangelsdorf, D. J., and Tontonoz, P. (2001) Proc Natl Acad Sci U S
A 98, 507-512.
3- Joseph, S. B., McKilligin, E., Pei, L., Watson, M. A., Collins, A. R.,
Laffitte, B. A., Chen, M., Noh, G., Goodman, J., Hagger, G. N., Tran,
J., Tippin, T. K., Wang, X., Lusis, A. J., Hsueh, W. A., Law, R. E.,
Collins, J. L., Willson, T. M., and Tontonoz, P. (2002) Proc Natl Acad
Sci U S A 99, 7604-7609.
4- Li, A. C., Brown, K. K., Silvestre, M. J., Willson, T. M., Palinski, W., and
Glass, C. K. (2000) J Clin Invest 106, 523-531.
5- Ricote, M., Li, A. C., Willson, T. M., Kelly, C. J., and Glass, C. K. (1998)
Nature 391, 79-82.