Quantitative estimations of the contribution of different bile acid pathways to total bile acid synthesis in the rat.
OBJECTIVE
Cholesterol degradation to bile acids occurs via "classic" or "alternative" bile acid biosynthetic pathways. The aim of this study was to assess the contributions of these two pathways to total bile acid synthesis in vivo.


METHODS
Rats with biliary fistulas were infused with squalestatin for 24 and 48 hours; specific activities of cholesterol 7 alpha-hydroxylase (C7 alpha H) and sterol 27-hydroxylase (S27H) and rates of bile acid synthesis were determined.


RESULTS
Continuous squalestatin infusion (15 micrograms/h) decreased C7 alpha H specific activities to 4% and 12% of paired biliary fistula controls at 24 and 48 hours, respectively (P < 0.05) without any changes in S27H specific activities (82% and 95% of controls). At 24 hours, bile acid synthesis decreased to 43% (P < 0.05) but returned to 87% at 48 hours (P = NS). Cholic acid synthesis decreased at 24 hours but returned to control levels at 48 hours. Similar changes in C7 alpha H, S27H, and bile acid synthesis were observed in primary rat hepatocytes after addition of squalestatin (1.0 mumol/L).


CONCLUSIONS
In the face of persistent suppression of C7 alpha H and the classic pathway, an alternative pathway becomes a main pathway of bile acid synthesis capable of generating cholic and chenodeoxycholic acids. The observed induction of bile acid synthesis via an alternative pathway or pathways represents an important mechanism for maintenance of cholesterol homeostasis in the rat.
Vlahcevic
Z R
ZR
Department of Medicine-Gastroenterology, McGuire Veterans Affairs Medical Center and Virginia Commonwealth University/Medical College of Virginia, Richmond, USA.
Stravitz
R T
RT
Heuman
D M
DM
Hylemon
P B
PB
Pandak
W M
WM
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000378:metabolism*; D001658:Biliary Fistula / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D053493:Cholestanetriol 26-Monooxygenase; D002790:Cholesterol 7-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019826:Cholic Acid; D002793:Cholic Acids / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D013250:Steroid Hydroxylases / Q000378:metabolism; D013997:Time Factors; D014233:Tricarboxylic Acids / Q000494:pharmacology
D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002793:Cholic Acids; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D002790:Cholesterol 7-alpha-Hydroxylase; D053493:Cholestanetriol 26-Monooxygenase; D019826:Cholic Acid