Regulation of bile acid synthesis. II. Effect of bile acid feeding on enzymes regulating hepatic cholesterol and bile acid synthesis in the rat.
Bile acid synthesis is believed to be regulated by bile salts returning to the liver via the portal vein and suppressing cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in the bile acid biosynthesis pathway. In order to characterize the relative effectiveness of bile salts in regulating bile acid synthesis, seven different bile acids were administered (1% w/w in chow) to rats over a 14-day period. Biliary bile salt composition was determined from bile samples obtained prior to killing; in all cases, the fed bile acid became the predominant bile salt in bile. The specific activities of microsomal cholesterol 7 alpha-hydroxylase, HMG-CoA reductase and acylconenzyme A:cholesterol acyltransferase were determined after killing. Hydrophilic bile salts (ursocholic, hyocholic, ursodeoxycholic and hyodeoxycholic) did not inhibit HMG-CoA reductase or cholesterol 7 alpha-hydroxylase activities. By contrast, more hydrophobic bile salts (cholic, chenodeoxycholic and deoxycholic) inhibited the activities of these two enzymes in order of increasing hydrophobicity. Neither hydrophobic nor hydrophilic bile salts inhibited acylcoenzyme A:cholesterol acyltransferase activity. No consistent effect of bile acid feeding on total microsomal cholesterol was observed. Based on the results of these studies, we propose that the hydrophilic-hydrophobic balance of the bile acid pool may play an important role in the regulation of bile acid synthesis. We postulate that the activities of cholesterol 7 alpha-hydroxylase and HMG-CoA reductase may be regulated by hydrophobic bile acid-induced changes in the lipid composition and physicochemical properties (fluidity) of the microsomal membranes to which both of these rate-limiting enzymes are attached.(ABSTRACT TRUNCATED AT 250 WORDS)
Heuman
D M
DM
Department of Medicine, Medical College of Virginia, Richmond 23298.
Vlahcevic
Z R
ZR
Bailey
M L
ML
Hylemon
P B
PB
D000818:Animals; D001647:Bile Acids and Salts / Q000008:administration & dosage / Q000096:biosynthesis* / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D005246:Feedback; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains; D013250:Steroid Hydroxylases / Q000378:metabolism*; D002785:Sterol O-Acyltransferase / Q000378:metabolism*
D001647:Bile Acids and Salts; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D013250:Steroid Hydroxylases; D002790:Cholesterol 7-alpha-Hydroxylase; D002785:Sterol O-Acyltransferase