In vivo regulation of human mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase. Studies in normal subjects.

Harwood, H. James; Bridge, D M; Stacpoole, Peter W.

doi:10.1172/jci112928

Cited by 37 publications

(22 citation statements)

References 67 publications

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“…In addition, urinary mevalonic acid has become an indicator of the effectiveness of statin drug treatment (Hiramatsu et al, 1998). However, our data are consistent with the data of Harwood et al (1987), indicating that the enzyme reaches its peak during the active feeding period of the animal, which in the case of rats would be during the dark period as opposed to the light period in humans. The presence of squalene epoxidase in cluster 4 further reinforces the validity of these observations.…”

Section: Discussionsupporting

confidence: 92%

Circadian Variations in Rat Liver Gene Expression: Relationships to Drug Actions

Almon

Yang

Lai³

et al. 2008

J Pharmacol Exp Ther

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Chronopharmacology is an important but under-explored aspect of therapeutics. Rhythmic variations in biological processes can influence drug action, including pharmacodynamic responses, due to circadian variations in the availability or functioning of drug targets. We hypothesized that global gene expression analysis can be useful in the identification of circadian-regulated genes involved in drug action. Circadian variations in gene expression in rat liver were explored using Affymetrix gene arrays. A rich time series involving animals analyzed at 18 time points within the 24-h cycle was generated. Of the more than 15,000 probe sets on these arrays, 265 exhibited oscillations with a 24-h frequency. Cluster analysis yielded five distinct circadian clusters, with approximately two thirds of the transcripts reaching maximal expression during the dark/active period of the animal. Of the 265 probe sets, 107 were identified as having potential therapeutic importance. The expression levels of clock genes were also investigated in this study. Five clock genes exhibited circadian variation in the liver, and data suggest that these genes may also be regulated by corticosteroids.

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Section: Discussionsupporting

confidence: 92%

Circadian Variations in Rat Liver Gene Expression: Relationships to Drug Actions

Almon

Yang

Lai³

et al. 2008

J Pharmacol Exp Ther

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“…IV Regardless of the precise mechanism for suppression of HMG CoA reductase activity in FH, it is noteworthy that subjects with heterozygous FH and those with receptor-defective homozygous disease are able to show increased enzyme activity after rapid lowering of circulating cholesterol by plasmapheresis, whereas patients with LDL-receptor-negative homozygous FH exhibit little or no change in HMG CoA reductase activity after plasmapheresis. These results, and our previous studies (10), indicate that the effect of plasma exchange on mononuclear leukocyte HMG CoA reductase activity is due principally, if not entirely, to stimulation of the monocyte enzyme. The stimulation of HMG CoA reductase activity and, presumably, cholesterol biosynthesis, by plasmapheresis may provide insight into the rapid restoration of circulating cholesterol levels after this procedure in patients with FH (26-28).…”

Section: Introductionsupporting

confidence: 81%

“…Studies in healthy human subjects (10) indicate that mononuclear leukocyte HMG CoA reductase activity responds to various nutritional and pharmacologic perturbations in a manner similar to that of the enzyme isolated from animal intestine or liver (1 1). In the present investigation we measured the activity and protein content of HMG CoA reductase in mononuclear cells obtained from healthy adults and patients with heterozygous or homozygous FH.…”

Section: Introductionmentioning

confidence: 99%

In vivo regulation of human mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase. Decreased enzyme catalytic efficiency in familial hypercholesterolemia.

Stacpoole¹,

Bridge²,

Alvarez³

et al. 1987

J. Clin. Invest.

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3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) controls the rate of cholesterol biosynthesis and is itself modulated through feedback suppression by internalized low density lipoprotein (LDL) cholesterol. We measured HMG CoA reductase protein concentration and microsomal enzyme activity in freshly isolated mononuclear leukocytes from normal individuals and patients with heterozygous or homozygous familial hypercholesterolemia (FH). Reductase protein concentration was similar in normal and heterozygous subjects, but was over twofold elevated in patients with homozygous FH. Reductase protein concentration was inversely related to LDL receptor status. Total activity and catalytic efficiency of reductase, however, were decreased in heterozygous and homozygous FH patients. The decrease in catalytic efficiency was not due to enzyme phosphorylation or thiol-disulfide formation. Reduction of plasma cholesterol concentration over 2 h by plasmapheresis increased reductase activity, the degree of which was directly proportional to the LDL-receptor status of the subjects.Decreased HMG CoA reductase activity and catalytic efficiency in mononuclear leukocytes and perhaps other cells in FH may represent a fundamental abnormality in the regulation of this enzyme independent of that induced by the LDL-receptor defect and may provide new insight into the control of cholesterol metabolism in FH.

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“…A decrease in serum cholesterol concentration causes a compensatory induction of HMG-CoA reductase and, hence, mevalonate synthesis in extrahepatic cells (6). We have recently shown that mevalonate promotes the growth in mice of tumors derived from human breast cancer cells, probably through enhanced proliferation (7).…”

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confidence: 99%

Statins and Cancer Development

Duncan

El-Sohemy

Archer

2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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There is epidemiologic evidence that the hydrophilic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor pravastatin increases the incidence of some extrahepatic cancers, although this finding has been attributed to chance. We hypothesize that pravastatin is able to promote the development of cancer by causing an induction of HMG-CoA reductase and, hence, mevalonate synthesis in extrahepatic tissues. We have shown that mevalonate, the product of HMG-CoA reductase, promotes the growth of breast cancer cells. Because there is no uptake of pravastatin by most extrahepatic cells, this statin will be unable to mitigate the increase in mevalonate synthesis in extrahepatic tissues that accompanies the decrease in circulating cholesterol caused by its inhibition of hepatic HMG-CoA reductase. (Cancer Epidemiol Biomarkers Prev 2005;14(8):1897 -8)

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In vivo regulation of human mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase. Studies in normal subjects.

Cited by 37 publications

References 67 publications

Circadian Variations in Rat Liver Gene Expression: Relationships to Drug Actions

Circadian Variations in Rat Liver Gene Expression: Relationships to Drug Actions

In vivo regulation of human mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase. Decreased enzyme catalytic efficiency in familial hypercholesterolemia.

Statins and Cancer Development

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