Abstract
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)
Highlights
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 HMGCoA reductase
The aims of the present study were %fold: first, to determine whether the increase in hepatic 3-hydroxy-3methylglutaryl coenqme A (HMG-CoA) reductase mRNA levels after LPS administration was due to increased transcription; second, to determine whether hepatic mRNA levels of other enzymes in the cholesterol biosynthetic pathway that are coordinately regulated with the HMGCoA reductase and low density lipoprotein (LDL) receptor, such as HMG-CoA synthase and farnesyl pyrophosphate (FPP) synthetase, are increased by LPS and cytokine treatment [12,13,14,15,16]; and third, to determine whether dietary manipulati-ons that regulate HMG-CoA reductase mRNA levels in liver,such as feeding cholesterol or bile resin binders [12, 13, 17, 18],alter the ability of LPS to increase hepatic HMG-CoA reductase mRNA levels
Studies have shown that both HMG-CoA synthase and FPP synthetase are coordinately regulated in parallel with HMG-CoA reductase and LDL receptors [6, 12,13,14,15,16]
Summary
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 HMGCoA reductase. An increase in hepatic cholesterol synthesis and/or HMG-CoAreductase activity has been shown in several different animal infections [2,3,4] These changes in lipid metabolism can be induced by administration of endotoxin (LPS) which mimics gram negative infections. Recent studies by our laboratory have demonstrated 'that in Syrian hamsters, LPS administration produces an increase in serum cholesterol levels that was primarily due to an increase in LDL cholesterol [5] An increase in both hepatic cholesterol synthesisand HMG-CoAreductase activity occurs in Syrian hamsters 16 h after treatment with LPS [5].
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