Feedback regulation of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity by dietary cholesterol is not due to altered mRNA levels.
Feeding rats diets containing 2% cholesterol markedly reduced hepatic 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity but had little effect on mRNA levels. Addition of mevalonolactone to the diet further decreased reductase activity independent of a change in mRNA levels. In contrast, farnesyl pyrophosphate synthetase mRNA levels and enzyme activity were decreased to similar degrees in response to dietary cholesterol. Addition of mevalonolactone to the diet did not further decrease farnesyl pyrophosphate synthetase activity. Dietary cholesterol and mevalonolactone had no effect on mRNA levels for "cellular nucleic acid-binding protein" which has been demonstrated to bind the sterol regulatory elements in the HMG-CoA reductase and farnesyl pyrophosphate synthetase promoters. Dietary cholesterol increased cholesterol 7 alpha-hydroxylase mRNA levels as expected. These results suggest that cholesterol-mediated feed-back regulation of hepatic HMG-CoA reductase gene expression does not occur at the level of transcription.
Ness
G C
GC
Department of Biochemistry and Molecular Biology, College of Medicine, University of South Florida, Tampa 33612.
Keller
R K
RK
Pendleton
L C
LC
D000818:Animals; D015152:Blotting, Northern; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D004122:Dimethylallyltranstransferase / Q000235:genetics / Q000378:metabolism; D005246:Feedback; D015971:Gene Expression Regulation, Enzymologic; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D002791:Cholesterol, Dietary; D012333:RNA, Messenger; C015367:mevalonolactone; D006903:Hydroxymethylglutaryl CoA Reductases; D002374:Catalase; D004122:Dimethylallyltranstransferase; D008798:Mevalonic Acid