Liver X receptors regulate adrenal cholesterol balance.
Cholesterol is the obligate precursor to adrenal steroids but is cytotoxic at high concentrations. Here, we show the role of the liver X receptors (LXRalpha and LXRbeta) in preventing accumulation of free cholesterol in mouse adrenal glands by controlling expression of genes involved in all aspects of cholesterol utilization, including the steroidogenic acute regulatory protein, StAR, a novel LXR target. Under chronic dietary stress, adrenal glands from Lxralphabeta-/- mice accumulated free cholesterol. In contrast, wild-type animals maintained cholesterol homeostasis through basal expression of genes involved in cholesterol efflux and storage (ABC transporter A1 [ABCA1], apoE, SREBP-1c) while preventing steroidogenic gene (StAR) expression. Upon treatment with an LXR agonist that mimics activation by oxysterols, expression of these target genes was increased. Basally, Lxralphabeta-/- mice exhibited a marked decrease in ABCA1 and a derepression of StAR expression, causing a net decrease in cholesterol efflux and an increase in steroidogenesis. These changes occurred under conditions that prevented the acute stress response and resulted in a phenotype more specific to the loss of LXRalpha, including hypercorticosteronemia, cholesterol ester accumulation, and adrenomegaly. These results imply LXRalpha provides a safety valve to limit free cholesterol levels as a basal protective mechanism in the adrenal gland, where cholesterol is under constant flux.
Cummins
Carolyn L
CL
Department of Pharmacology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050, USA.
Volle
David H
DH
Zhang
Yuan
Y
McDonald
Jeffrey G
JG
Sion
Benoît
B
Lefrançois-Martinez
Anne-Marie
AM
Caira
Françoise
F
Veyssière
Georges
G
Mangelsdorf
David J
DJ
Lobaccaro
Jean-Marc A
JM
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000311:Adrenal Glands / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D006984:Hypertrophy; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D009930:Organic Chemicals / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; C423914:LG 268; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D009930:Organic Chemicals; D057093:Orphan Nuclear Receptors; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D047488:Retinoid X Receptors; D000098682:Steroidogenic Acute Regulatory Protein; D002784:Cholesterol; D003345:Corticosterone