Inhibition of LXRalpha signaling by vitamin D receptor: possible role of VDR in bile acid synthesis.
The expression of cholesterol 7alpha-hydroxylase (CYP7alpha), the rate-limiting enzyme in the catabolism of cholesterol to bile acid, is stimulated by oxysterol receptor, liver X receptor alpha (LXRalpha) and negatively regulated by a bile acid receptor, farnesoid X receptor. In the current study, we demonstrated that 1,25-(OH)(2)D3 blunted the LXRalpha-mediated induction of CYP7alpha mRNA in H4IIE rat hepatoma cells. In co-transfection experiments in HepG2 cells, VDR repressed the activity of rat CYP7alpha promoter in a ligand-dependent manner through inhibition of LXRalpha signaling. We also confirmed the ability of VDR to repress LXRalpha transcriptional activation using a synthetic LXRalpha responsive reporter. Deletion analyses revealed that the ligand-binding domain of VDR was required for the suppression and the DNA-binding domain was dispensable. Given the fact that VDR can be activated by the secondary bile acid as well as 1,25-(OH)(2)D3, the crosstalk between LXRalpha and VDR signaling in regulation of bile acid metabolism provides a possible contribution of VDR to modulate bile acid and cholesterol homeostasis, and highlights a physiological function of VDR beyond calcium metabolism in the body.
Jiang
Wei
W
Department of Endocrinology, The First Clinical College, Harbin Medical University, Harbin 150001, China.
Miyamoto
Takahide
T
Kakizawa
Tomoko
T
Nishio
Shin-Ich
SI
Oiwa
Ako
A
Takeda
Teiji
T
Suzuki
Satoru
S
Hashizume
Kiyoshi
K
D000818:Animals; D001647:Bile Acids and Salts; D019556:COS Cells; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; C074477:1,25-dihydroxy-23-azavitamin D3; D002790:Cholesterol 7-alpha-Hydroxylase; D002117:Calcitriol