Liver X receptor (LXR)-β regulation in LXRα-deficient mice:: Implications for therapeutic targeting

The nuclear receptors liver X receptor (LXR) LXR alpha and LXR beta are differentially expressed ligand-activated transcription factors that induce genes controlling cholesterol homeostasis and lipogenesis. Synthetic ligands for both receptor subtypes activate ATP binding cassette transporter A1 (ABCA1)-mediated cholesterol metabolism, increase reverse cholesterol transport, and provide atheroprotection in mice. However, these ligands may also increase hepatic triglyceride (TG) synthesis via a sterol response element binding protein 1c (SREBP-1c)-dependent mechanism through a process reportedly regulated by LXR alpha. We studied pan-LXR alpha/beta agonists in LXR alpha knockout mice to assess the contribution of LXR beta to the regulation of selected target genes. In vitro dose-response studies with macrophages from LXR alpha -/- and beta -/- mice confirm an equivalent role for LXR alpha and LXR beta in the regulation of ABCA1 and SREBP-1c gene expression. Cholesterol-efflux studies verify that LXR beta can drive apoA1-dependent cholesterol mobilization from macrophages. The in vivo role of LXR beta in liver was further evaluated by treating LXR alpha -/- mice with a pan-LXR alpha/beta agonist. High-density lipoprotein (HDL) cholesterol increased without significant changes in plasma TG or very low density lipoprotein. Analysis of hepatic gene expression consistently revealed less activation of ABCA1 and SREBP-1c genes in the liver of LXR alpha null animals than in treated wild-type controls. In addition, hepatic CYP7A1 and several genes involved in fatty acid/TG biosynthesis were not induced. In peripheral tissues from these LXR alpha-null mice, LXR beta activation increases ABCA1 and SREBP-1c gene expression in a parallel manner. However, putative elevation of SREBP-1c activity in these tissues did not cause hypertriglyceridemia. In summary, selective LXR beta activation is expected to stimulate ABCA1 gene expression in macrophages, contribute to favorable HDL increases, but circumvent hepatic LXR alpha-dominated lipogenesis.