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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
- Source :
- British Journal of Pharmacology, 7, 162, 1553-1563
- Publication Year :
- 2011
-
Abstract
- 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. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
- Subjects :
- Benzylamines
Apolipoprotein E3
Mice, Transgenic
Benzoates
lipids
Mice
Life
Animals
Humans
Triglycerides
Liver X Receptors
Hypertriglyceridemia
Aniline Compounds
Dose-Response Relationship, Drug
Atherosclerosis
Lipid Metabolism
Orphan Nuclear Receptors
Research Papers
reverse cholesterol transport
Fatty Liver
Mice, Inbred C57BL
Thiazoles
Cholesterol
Liver
Health
inflammation
Cytokines
Female
EELS - Earth, Environmental and Life Sciences
MHR - Metabolic Health Research
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- British Journal of Pharmacology, 7, 162, 1553-1563
- Accession number :
- edsair.pmid.dedup....4fbdec069e409f272a9b66530559cfec