Increased bile acid pool inhibits cholesterol 7 alpha-hydroxylase in cholesterol-fed rabbits.
OBJECTIVE
Cholesterol feeding unexpectedly inhibits cholesterol 7 alpha-hydroxylase in rabbits. The aim of this study was to explore the mechanism.


METHODS
Twenty male New Zealand white rabbits were fed regular chow with and without 2% cholesterol for 10 days followed by 7 days of bile drainage. The activities of hepatic cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase that control bile acid synthesis in classic and alternative pathways were related to the size and composition of bile acid pool.


RESULTS
After feeding cholesterol, plasma and hepatic cholesterol concentrations increased, the bile acid pool doubled (from 254 +/- 44 to 533 +/- 51 mg; P < 0.001), cholesterol 7 alpha-hydroxylase activity decreased 68% (P < 0.01), but sterol 27-hydroxylase activity increased 66% (P < 0.05) with increased cholic acid synthesis (P < 0.01). Bile drainage in the cholesterol-fed rabbits depleted the bile acid pool and stimulated down-regulated cholesterol 7 alpha-hydroxylase activity 11.4-fold (P < 0.001), although hepatic cholesterol remained elevated. Hepatic sterol 27-hydroxylase activity was unaffected.


CONCLUSIONS
Feeding cholesterol increased hepatic cholesterol and stimulated sterol 27-hydroxylase and alternative bile acid synthesis, which expanded the bile acid pool and inhibited cholesterol 7 alpha-hydroxylase in rabbits. In distinction, hepatic sterol 27-hydroxylase was insensitive to changes in the bile acid pool.
Xu
G
G
Medical Service, Veterans Affairs Medical Center, East Orange, New Jersey, USA.
Salen
G
G
Shefer
S
S
Tint
G S
GS
Kren
B T
BT
Nguyen
L B
LB
Steer
C J
CJ
Chen
T S
TS
Salen
L
L
Greenblatt
D
D
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D019826:Cholic Acid; D002793:Cholic Acids / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003840:Deoxycholic Acid / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008930:Mitochondria, Liver / Q000201:enzymology; D011817:Rabbits; D012016:Reference Values; D013250:Steroid Hydroxylases / Q000378:metabolism
D001647:Bile Acids and Salts; D002791:Cholesterol, Dietary; D002793:Cholic Acids; D003840:Deoxycholic Acid; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D013250:Steroid Hydroxylases; D002790:Cholesterol 7-alpha-Hydroxylase; D053493:Cholestanetriol 26-Monooxygenase; D019826:Cholic Acid