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Could Lipids Be a Key to Control Inflammation?

Gretchen Henkel  |  Issue: March 2011  |  March 18, 2011

Dr. Tietge’s group designed a study, published in Gastroenterology, to explore the relevance of biliary sterol secretion, supposedly the final step in the reverse cholesterol transport pathway.3 By ligating the bile ducts of mice and following the macrophage to feces RCT, they demonstrated that RCT requires biliary cholesterol secretion.

Dr. Tietge also touched on another intriguing aspect of the relationship between cholesterol metabolism and the inflammatory process—namely, that plasma levels of HDL are markedly decreased in acute as well as chronic inflammatory states, such as RA. Knowing that acute inflammation induces changes in HDL composition, his group wanted to address whether LXR activation can improve the inflammation-induced reduction in RCT. The study design, he said, aimed “to test an LXR agonist for the treatment of metabolic alterations as a consequence of inflammation.”

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In this 30-hour experiment, mice received an LXR agonist either four hours before or four hours after the inflammatory stimulus LPS was administered. LXR activation increased the reverse cholesterol transport by two-fold in wild-type mice who were given PBS. Also, consistent with previous data, RCT was significantly decreased in mice injected with LPS. Pre-treatment with an LXR agonist reversed this phenotype and increased the RCT to the levels shown in the wild-type mice. In other words, Dr. Tietge concluded, “LXR activation promotes pathways resulting in cholesterol elimination from the body.”

We now know, stated Dr. Tietge, that “LXR can directly increase the expression of antiinflammatory genes, and more importantly, that LXR mediates the transrepression of a large set of genes induced by inflammation.”

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Most animal studies have shown antiinflammatory effects of LXR agonists given before or together with an inflammatory stimulus. However, Dr. Tietge noted, this “does not represent a realistic scenario for clinical applications,” because patients present when the inflammatory process has already begun.

And, he pointed out, we cannot simply assume that giving LXR agonists will be the solution to interrupting atherogenesis. Depending on the timing of the treatment, LXR agonists might even act as proinflammatories. When long-term treatment for metabolic disease is considered, exacerbation of inflammatory responses or promotion of tumor growth might occur, further limiting the applicability of LXR agonists for this indication.

Dr. Tietge concluded his talk by offering some perspectives on the directions that future research might take. For instance, more research is required on the timing of LXR agonist administration, especially in the context of LXR expression and coactivator/corepressor recruitment. It also will be necessary to further understand the contribution of potential differential effects of LXR isoforms and specific coactivators or corepressor complexes. Armed with this knowledge, researchers will be able to design more efficient therapeutic strategies targeting this promising pathway.

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Filed under:ConditionsRheumatoid Arthritis Tagged with:Cardiovascular diseasecholesterolhigh-density lipoproteininflammationLipidRheumatoid arthritis

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