gw-3965 has been researched along with Hypertriglyceridemia* in 2 studies
2 other study(ies) available for gw-3965 and Hypertriglyceridemia
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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.
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.. APOE*3Leiden mice were fed an atherogenic diet alone or supplemented with either AZ876 (5 or 20µmol·kg(-1) ·day(-1) ) or GW3965 (17µmol·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.. 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.. 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. Topics: Aniline Compounds; Animals; Apolipoprotein E3; Atherosclerosis; Benzoates; Benzylamines; Cholesterol; Cytokines; Dose-Response Relationship, Drug; Fatty Liver; Female; Humans; Hypertriglyceridemia; Inflammation; Lipid Metabolism; Lipids; Liver; Liver X Receptors; Mice; Mice, Inbred C57BL; Mice, Transgenic; Orphan Nuclear Receptors; Thiazoles; Triglycerides | 2011 |
Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator.
Liver X receptors (LXRs) are ligand-activated transcription factors that belong to the nuclear receptor superfamily. LXRs activate transcription of a spectrum of genes that regulate reverse cholesterol transport, including the ATP binding cassette transporter A1 (ABCA1), and raise HDL cholesterol (HDL-C) levels. However, LXR agonists also induce genes that stimulate lipogenesis, including the sterol response element binding protein (SREBP1-c) and fatty acid synthetase (FAS). The induction of these genes in the liver cause increased hepatic triglyceride synthesis, hypertriglyceridemia, and hepatic steatosis. As LXR response elements have been identified in these promoters, it is not clear if these two processes can be separated. Herein, we demonstrate that plasma HDL-C elevation and intestinal ABCA1 induction can occur with relatively little induction of FAS and SREBP1-c in mouse liver via a selective LXR modulator GW3965. This is in contrast to the strong induction of hepatic lipogenic genes by the well-characterized LXR agonist T0901317 (T317). Consistent with the in vivo results, GW3965 is a very weak LXR activator compared with T317 in human hepatoma cells. GW3965-liganded LXR recruits selected coactivators less effectively than T317 and may explain in part the tissue selective gene induction. This demonstration that tissue and gene selective modulation is possible with selective LXR modulators has positive implications for the development of this class of antiatherosclerotic agents. Topics: Animals; Benzoates; Benzylamines; Cholesterol, HDL; DNA-Binding Proteins; Fatty Liver; Hypertriglyceridemia; Ligands; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Organ Specificity; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear | 2004 |