In vitro
GW3965 can inhibit liver X receptor (LXR), which can activate genes that regulate lipid and cholesterol metabolism. Treatment of primary human hepatocytes with GW3965 results in reduced output of bile acids and very low density lipoprotein triglycerides and induced expression of adipose differentiation-related protein accompanied by increased lipid storage. In pentobarbital-anesthetized male Sprague-Dawley rats, after oral administration of GW3965 (10 mg kg(-1), q.d.), GW3965 dosing blunted the vasopressor effect of Ang II, which was significantly different with the 0.3 and 3 microg kg(-1) doses. GW3965 decreased Ang II-mediated vasopressor responses coincident with a trend toward reduced ATR gene expression, suggesting that LXR agonists could affect vascular reactivity. GW3965 could modulate the inflammatory status of human pancreatic islets. Treatment of LPS-stimulated human islets with the synthetic LXR agonist GW3965 (1 micromol/l) for 24 h reduced mRNA and protein levels of selected pro-inflammatory cytokines (IL-8, monocyte chemotactic protein-1 and tissue factor). Even liver X receptor (LXR) agonism has previously been shown to increase insulin release from pancreatic islets and reduce inflammation in leucocytes, GW3965,as a agonist of agonist, had no adverse effect on insulin secretion, islet viability or apoptosis.
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