Editorial Slides VP Watch, January 22, 2003, Volume 3, Issue 3

Does LXR Links Lipid Metabolism to Inflammation, or PPAR?

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.

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.

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).

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).

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.

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)

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.

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.

The American Society for Biochemistry and Molecular Biology

From JBC January 16, 2003 (1)

The American Society for Biochemistry and Molecular Biology.

From JBC January 16, 2003 (1)

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.

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).

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.

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.

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?

Conclusion:

Does LXR agonist, GW3965, presents a likely candidate for stabilization of vulnerable plaque?

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.