Differential regulation of rat and human CYP7A1 by the nuclear oxysterol receptor liver X receptor-alpha.
In rodent liver, transcription of the gene encoding cholesterol 7alpha-hydroxylase (CYP7A1), which catalyzes the rate-limiting step in the classic bile acid synthetic pathway, is stimulated by the liver X receptor alpha (LXRalpha), a nuclear receptor for oxysterol metabolites of cholesterol. This feed-forward regulatory loop provides a mechanism for the elimination of excess cholesterol from the body. In this report, we demonstrate that in primary cultures of human hepatocytes, activation of LXRalpha has the opposite effect, repressing CYP7A1 expression. This repression is mediated, at least in part, through induction of the orphan nuclear receptor, short heterodimer partner (SHP), which is also induced by bile acids. We demonstrate that SHP is regulated directly by LXRalpha through a DNA response element that overlaps with the previously characterized bile acid response element. Our data reveal a fundamental difference in the regulation of CYP7A1 in rodent and human hepatocytes and provide evidence that different species employ distinct molecular strategies to regulate cholesterol homeostasis.
Goodwin
Bryan
B
Nuclear Receptor Discovery Research, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA. brian.j.goodwin@gsk.com
Watson
Michael A
MA
Kim
Hwajin
H
Miao
Ji
J
Kemper
Jongsook Kim
JK
Kliewer
Steven A
SA
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D015152:Blotting, Northern; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins; D024202:Electrophoretic Mobility Shift Assay; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D006888:Hydroxycholesterols / Q000494:pharmacology; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D013449:Sulfonamides; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000924:Anticholesteremic Agents; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C000605215:Nr1h3 protein, rat; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C099713:nuclear receptor subfamily 0, group B, member 2; C003585:22-hydroxycholesterol