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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
Author(s) -
van der Hoorn JWA,
Lindén D,
Lindahl U,
Bekkers MEA,
Voskuilen M,
Nilsson R,
Oscarsson J,
Lindstedt EL,
Princen HMG
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01168.x
Subject(s) - triglyceride , agonist , endocrinology , medicine , receptor , apolipoprotein e , liver x receptor , chemistry , cholesterol , nuclear receptor , biochemistry , disease , transcription factor , gene
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.