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Low dose of the liver X receptor agonist, AZ876, reduces atherosclerosis in APOE*3Leiden mice without affecting liver or plasma triglyceride levels
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2011 (English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 162, no 7, 1553-1563 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE:

Liver X receptor (LXR) agonists are atheroprotective but often induce hypertriglyceridaemia and liver steatosis. We investigated the effect of a novel high-affinity LXR activator, AZ876, on plasma lipids, inflammation and atherosclerosis, and compared the effects with another LXR agonist, GW3965.

EXPERIMENTAL APPROACH:

APOE*3Leiden mice were fed an atherogenic diet alone or supplemented with either AZ876 (5 or 20 µmol·kg−1·day−1) or GW3965 (17 µmol·kg−1·day−1) for 20 weeks. Total cholesterol and triglyceride levels were measured using commercial kits. Plasma cytokines were determined by using bead-based multiplex suspension array kits with the Luminex technology. Atherosclerosis was assessed histochemically and lesion composition was assessed by immunohistochemical methods.

KEY RESULTS:

Low-dose AZ876 had no effect on plasma or liver lipids, whereas high-dose AZ876 increased plasma triglycerides (+110%) and reduced cholesterol (-16%) compared with controls. GW3965 increased plasma triglycerides (+70%). Low-dose AZ876 reduced lesion area (-47%); and high-dose AZ876 strongly decreased lesion area (-91%), lesion number (-59%) and severity. In either dose, AZ876 did not affect lesion composition. GW3965 reduced atherosclerosis and collagen content of lesions (-23%; P < 0.01). High-dose AZ876 and GW3965, but not low-dose AZ876, reduced inflammation as reflected by lower cytokine levels and vessel wall activation.

CONCLUSIONS AND IMPLICATIONS:

We have identified a novel LXR agonist that when given in a low dose inhibits the progression of atherosclerosis without inducing anti-inflammatory effects, liver steatosis or hypertriglyceridaemia. Therefore, the primary protective action of a low-dose AZ876 is likely to be an increased reverse cholesterol transport.

Place, publisher, year, edition, pages
2011. Vol. 162, no 7, 1553-1563 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-169176DOI: 10.1111/j.1476-5381.2010.01168.xPubMedID: 21175581OAI: oai:DiVA.org:uu-169176DiVA: diva2:505264
Available from: 2012-02-23 Created: 2012-02-23 Last updated: 2017-12-07Bibliographically approved

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