Different roles of liver X receptor α and β in lipid metabolism: Effects of an α-selective and a dual agonist in mice deficient in each subtype

Liver X receptor (LXR) α and LXRβ are closely related nuclear receptors that respond to elevated levels of intracellular cholesterol by enhancing transcription of genes that control cholesterol efflux and fatty acid biosynthesis. The consequences of inactivation of either LXR isoform have been thoroughly studied, as have the effects of simultaneous activation of both LXRα and LXRβ by synthetic compounds. We here describe the effects of selective activation of LXRα or LXRβ on lipid metabolism. This was accomplished by treating mice genetically deficient in either LXRα or LXRβ with an agonist with equal potency for both isoforms (Compound B) or a synthetic agonist selective for LXRα (Compound A). We also determined the effect of these agonists on gene expression and cholesterol efflux in peritoneal macrophages derived from wild-type and knockout mice. Both compounds raised HDL-cholesterol and increased liver triglycerides in wild-type mice; in contrast, in mice deficient in LXRα, Compound B increased HDL-cholesterol but did not cause hepatic steatosis. Compound B induced ATP-binding cassette transporter (ABC) A1 expression and stimulated cholesterol efflux in macrophages from both LXRα and LXRβ-deficient mice. Our data lend further experimental support to the hypothesis that LXRβ-selective agonists may raise HDL-cholesterol and stimulate macrophage cholesterol efflux without causing liver triglyceride accumulation.