Discordant regulation of proteins of cholesterol metabolism during the acute phase response.
Recent studies have shown that the administration of endotoxin (LPS) and cytokines to Syrian hamsters increases serum cholesterol levels, hepatic cholesterol synthesis, and the activity, protein levels, and mRNA levels of hepatic HMG-CoA reductase. Despite the greater than 10-fold increase in HMG-CoA reductase mRNA levels, LPS had only minimal effects on hepatic LDL receptor mRNA levels. In the present study, we demonstrate that LPS increases the transcription rate in the liver of HMG-CoA reductase mRNA approximately 4- to 5-fold without affecting LDL receptor mRNA transcription. Most stimuli that regulate HMG-CoA reductase and LDL receptor mRNA levels also regulate, in parallel, HMG-CoA synthase and farnesyl pyrophosphate (FPP) synthetase. However, in chow-fed animals, LPS and cytokines (TNF, IL-1, TNF + IL-1) increased hepatic HMG-CoA reductase mRNA levels without increasing LDL receptor, HMG-CoA synthase, or FPP synthetase mRNA levels. The feeding of cholesterol or bile resin binders regulates the mRNA levels of HMG-CoA reductase, LDL receptor, HMG-CoA synthase, and FPP synthetase. In both cholesterol- and colestipol-fed animals, LPS increased HMG-CoA reductase mRNA levels while either decreasing or causing minimal increases in the mRNA levels of the other proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
Feingold
K R
KR
Department of Medicine, University of California, San Francisco, USA.
Pollock
A S
AS
Moser
A H
AH
Shigenaga
J K
JK
Grunfeld
C
C
D000210:Acute-Phase Reaction / Q000139:chemically induced / Q000201:enzymology*; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D003084:Colestipol / Q000008:administration & dosage; D006224:Cricetinae; D004032:Diet; D004122:Dimethylallyltranstransferase / Q000235:genetics; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics; D008070:Lipopolysaccharides; D008099:Liver / Q000201:enzymology; D008297:Male; D008647:Mesocricetus; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D014158:Transcription, Genetic
D002791:Cholesterol, Dietary; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011973:Receptors, LDL; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D006904:Hydroxymethylglutaryl-CoA Synthase; D004122:Dimethylallyltranstransferase; D003084:Colestipol