The
nuclear receptors liver X receptor (LXR) LXRalpha and LXRbeta 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 LXRalpha. We studied pan-LXRalpha/beta agonists in LXRalpha knockout mice to assess the contribution of LXRbeta to the regulation of selected target genes. In vitro dose-response studies with macrophages from LXRalpha-/- and beta-/- mice confirm an equivalent role for LXRalpha and LXRbeta in the regulation of ABCA1 and
SREBP-1c gene expression.
Cholesterol-efflux studies verify that LXRbeta can drive apoA1-dependent
cholesterol mobilization from macrophages. The in vivo role of LXRbeta in liver was further evaluated by treating LXRalpha-/- mice with a pan-LXRalpha/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 LXRalpha 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 LXRalpha-null mice, LXRbeta 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 LXRbeta activation is expected to stimulate ABCA1 gene expression in macrophages, contribute to favorable HDL increases, but circumvent hepatic LXRalpha-dominated lipogenesis.