Removal of the bile acid pool upregulates cholesterol 7alpha-hydroxylase by deactivating FXR in rabbits.
We investigated the role of the orphan nuclear receptor farnesoid X receptor (FXR) in the regulation of cholesterol 7alpha-hydroxylase (CYP7A1), using an in vivo rabbit model, in which the bile acid pool, which includes high affinity ligands for FXR, was eliminated. After 7 days of bile drainage, the enterohepatic bile acid pool, in both New Zealand White and Watanabe heritable hyperlipidemic rabbits, was depleted. CYP7A1 activity and mRNA levels increased while FXR was deactivated as indicated by reduced FXR protein and changes in the expression of target genes that served as surrogate markers of FXR activation in the liver and ileum, respectively. Hepatic bile salt export pump mRNA levels and ileal bile acid-binding protein decreased while sterol 12alpha-hydroxylase and sodium/taurocholate cotransporting polypeptide mRNA levels increased in the liver. In addition, hepatic FXR mRNA levels decreased significantly. The data, taken together, indicate that FXR was deactivated when the bile acid pool was depleted such that CYP7A1 was upregulated. Further, lack of the high affinity ligand supply was associated with downregulation of hepatic FXR mRNA levels.
Xu
Guorong
G
Medical Service, G1 Lab (15A), Veterans Affairs Medical Center, 385 Tremont Avenue, East Orange, NJ 07018-1095, USA. xugu@umdnj.edu
Pan
Lu-xing
LX
Erickson
Sandra K
SK
Forman
Barry M
BM
Shneider
Benjamin L
BL
Ananthanarayanan
M
M
Li
Xiaogui
X
Shefer
Sarah
S
Balasubramanian
N
N
Ma
Lin
L
Asaoka
Hitoshi
H
Lear
Steven R
SR
Nguyen
Lien B
LB
Dussault
Isabelle
I
Suchy
Frederick J
FJ
Tint
G Stephen
GS
Salen
Gerald
G
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004322:Drainage / Q000379:methods; D006913:Hydroxysteroid Dehydrogenases; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear; D013253:Steroid 12-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism; D027981:Symporters; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation; D000099150:Receptor, Farnesoid X-Activated; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D002790:Cholesterol 7-alpha-Hydroxylase; D003577:Cytochrome P-450 Enzyme System; D004268:DNA-Binding Proteins; D006913:Hydroxysteroid Dehydrogenases; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013253:Steroid 12-alpha-Hydroxylase; D013250:Steroid Hydroxylases; D027981:Symporters; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C037643:bile acid binding proteins; C071908:sodium-bile acid cotransporter; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)