Low dose of the liver X receptor agonist, AZ876, reduces atherosclerosis in APOE*3Leiden mice without affecting liver or plasma triglyceride levels
| Autor: | Ulf Lindahl, Hmg Princen, El Lindstedt, M Voskuilen, Jwa van der Hoorn, Jan Oscarsson, Daniel Lindén, Mea Bekkers, Ralf Nilsson |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Pharmacology
Agonist Apolipoprotein E 0303 health sciences medicine.medical_specialty Cholesterol medicine.drug_class Reverse cholesterol transport Hypertriglyceridemia Fatty liver 030204 cardiovascular system & hematology Biology medicine.disease 3. Good health Lesion 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology chemistry Internal medicine medicine medicine.symptom Liver X receptor 030304 developmental biology |
| Zdroj: | British Journal of Pharmacology. 162:1553-1563 |
| ISSN: | 0007-1188 |
| DOI: | 10.1111/j.1476-5381.2010.01168.x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|