Liver X receptor (LXR)-beta regulation in LXRalpha-deficient mice: implications for therapeutic targeting.
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.
Quinet
Elaine M
EM
Department of Cardiovascular/Metabolic Diseases, Wyeth Research, 500 Arcola Road, RN2229, Collegeville, PA 19426, USA. quinete@wyeth.com
Savio
Dawn A
DA
Halpern
Anita R
AR
Chen
Liang
L
Schuster
Gertrude U
GU
Gustafsson
Jan-Ake
JA
Basso
Mike D
MD
Nambi
Ponnal
P
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000097:blood; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; C506119:Insig1 protein, mouse; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D008565:Membrane Proteins; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1