Differing effects of cholesterol and taurocholate on steady state hepatic HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities and mRNA levels in the rat.
We investigated the effects of cholesterol, cholestyramine, and taurocholate feeding on steady state specific activities and mRNA levels of hepatic 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase and cholesterol 7 alpha-hydroxylase in the rat. Interruption of the enterohepatic circulation of bile acids (cholestyramine feeding) increased total HMG-CoA reductase activity 5-fold. Cholesterol and taurocholate administration suppressed total microsomal HMG-CoA reductase activities 87% and 65%, respectively. HMG-CoA reductase mRNA levels increased 3-fold with cholestyramine, did not decrease significantly with cholesterol feeding, but were markedly decreased after taurocholate treatment. Cholesterol 7 alpha-hydroxylase activity increased 4-fold with cholestyramine and 29% during cholesterol feeding, but decreased 64% with taurocholate. Cholesterol 7 alpha-hydroxylase mRNA levels rose 150% and 50% with cholestyramine and cholesterol feeding, respectively, but decreased 73% with taurocholate. The administration of cholesterol together with taurocholate prevented the decline in cholesterol 7 alpha-hydroxylase mRNA levels, but inhibition of enzyme activity persisted (-76%). Hepatic microsomal cholesterol concentrations increased 2-fold with cholesterol feeding but did not change with taurocholate or cholestyramine treatment. These results demonstrate that mRNA levels of HMG-CoA reductase are controlled by the hepatic taurocholate flux, whereas mRNA levels of cholesterol 7 alpha-hydroxylase are controlled by the cholesterol substrate supply. These end products, cholesterol and bile acids, exert post-transcriptional regulation on HMG-CoA reductase and cholesterol 7 alpha-hydroxylase, respectively.
Shefer
S
S
Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark 07103.
Nguyen
L B
LB
Salen
G
G
Ness
G C
GC
Chowdhary
I R
IR
Lerner
S
S
Batta
A K
AK
Tint
G S
GS
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000032:analysis; D002784:Cholesterol / Q000378:metabolism / Q000494:pharmacology*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002792:Cholestyramine Resin / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis* / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013656:Taurocholic Acid / Q000494:pharmacology
D001647:Bile Acids and Salts; D012333:RNA, Messenger; D002792:Cholestyramine Resin; D013656:Taurocholic Acid; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase