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Citations to this article

Feedback Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Livers of Mice Treated with Mevinolin, a Competitive Inhibitor of the Reductase
Toru Kita, … , Michael S. Brown, Joseph L. Goldstein
Toru Kita, … , Michael S. Brown, Joseph L. Goldstein
Published November 1, 1980
Citation Information: J Clin Invest. 1980;66(5):1094-1100. https://doi.org/10.1172/JCI109938.
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Research Article

Feedback Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Livers of Mice Treated with Mevinolin, a Competitive Inhibitor of the Reductase

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Abstract

Compactin (ML-236B) and the related compound, mevinolin, are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase), the rate-controlling enzyme in cholesterol synthesis. Previous studies have shown that administration of compactin to cultured cells elicits a compensatory increase in the amount of HMG CoA reductase in the cells. A similar increase in HMG CoA reductase has been reported in livers of rats and mice that have been treated with compactin. In this study, we explore the mechanism for the mevinolin-mediated increase in hepatic HMG CoA reductase in mice that have been fed a control diet and a 2% cholesterol diet. Administration of mevinolin to mice on a control diet produced a 6- to 10-fold increase in the amount of HMG CoA reductase in liver microsomes. When mice were fed the cholesterol-enriched diet, cholesterol accumulated in the liver and HMG CoA reductase declined by 90%. The administration of mevinolin to cholesterol-fed mice produced a three to eightfold increase in HMG CoA reductase. Despite the abundant amount of cholesterol that was already present in the livers of the mevinolin-treated, cholesterol-fed animals, their elevated HMG CoA reductase could be rapidly suppressed by the subcutaneous injection of small amounts of mevalonate, the product of HMG CoA reductase. These data are compatible with the existence in mouse liver of a multivalent feedback regulatory mechanism for HMG CoA reductase in which suppression of the enzyme requires both a sterol and a nonsterol substance derived from mevalonate. By blocking mevalonate synthesis, mevinolin activates this regulatory mechanism, and this in turn causes an increase in hepatic HMG CoA reductase. The ability to suppress the elevated HMG CoA reductase with mevalonate may prove useful in potentiating the effectiveness of mevinolin as a hypocholesterolemic agent.

Authors

Toru Kita, Michael S. Brown, Joseph L. Goldstein

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 1988 1987 1986 1985 1984 1983 1982 1981 1965 Total
Citations: 1 3 2 6 3 5 1 7 2 7 7 6 7 3 12 8 6 10 8 13 11 8 10 4 7 12 5 7 7 2 8 2 9 5 8 8 8 3 1 6 4 3 4 2 1 1 263
Citation information
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Citations to this article in year 2008 (10)

Title and authors Publication Year
Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase
RA DeBose-Boyd
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Modelling neurofibromatosis type 1 tibial dysplasia and its treatment with lovastatin
M Kolanczyk, J Kühnisch, N Kossler, M Osswald, S Stumpp, B Thurisch, U Kornak, S Mundlos
BMC Medicine 2008
Lovastatin effect in rat neuroblasts of the CNS: inhibition of cap-dependent translation
MO Santa-Catalina, LJ Garcia-Marin, MJ Bragado
Journal of Neurochemistry 2008
Atorvastatin has hypolipidemic and anti-inflammatory effects in apoE/LDL receptor-double-knockout mice
P Nachtigal, N Pospisilova, G Jamborova, K Pospechova, D Solichova, C Andrys, P Zdansky, S Micuda, V Semecky
Life Sciences 2008
Simvastatin impairs humoral and cell-mediated immunity in mice by inhibiting lymphocyte homing, T-cell activation and antigen cross-presentation
C Ulivieri, D Fanigliulo, D Benati, FL Pasini, CT Baldari
European Journal of Immunology 2008
Lovastatin inhibits oxidized low-density lipoprotein-induced plasminogen activator inhibitor and transforming growth factor-β1 expression via a decrease in Ras/extracellular signal-regulated kinase activity in mesangial cells
CY Song, BC Kim, HS Lee
Translational Research 2008
Alleviative effects of s-allyl cysteine and s-ethyl cysteine on MCD diet-induced hepatotoxicity in mice
C Lin, M Yin, W Liu
Food and Chemical Toxicology 2008
Unsaturated Fatty Acids Inhibit Proteasomal Degradation of Insig-1 at a Postubiquitination Step
JN Lee, X Zhang, JD Feramisco, Y Gong, J Ye
The Journal of biological chemistry 2008
Simvastatin Treatment Shows No Effect on the Incidence of Cerebral Malaria or Parasitemia during Experimental Malaria
R Kobbe, N Schreiber, J May, T Jacobs
Antimicrobial agents and chemotherapy 2008

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