Dietary phytosterols are cholesterol-lowering agents that interfere with the intestinal absorption of cholesterol. In the present study, we have studied their effects on cholesterol biosynthesis in human cells, particularly in the sterol-conversion pathway. For this, both Caco-2 (intestinal mucosa) and HL-60 (promyelocytic) human cell lines were incubated with [14C]acetate, and the incorporation of radioactivity into sterols was determined using HPLC and radioactivity detection online. Sterols containing a double bond at C-22 in the side chain (stigmasterol, brassicasterol and ergosterol) dramatically inhibited the activity of sterol Δ24-reductase, as indicated by the decrease in radioactivity incorporation into cholesterol and the accumulation of its precursors (mainly desmosterol). Phytosterols with the saturated side chain (β-sitosterol and campesterol) were inactive in this regard. The inhibition of sterol 24-reductase was confirmed in rat liver microsomes by using 14C-labelled desmosterol as the substrate. The 22-unsaturated phytosterols acted as competitive inhibitors of sterol 24-reductase, with Ki values (41.1, 42.7 and 36.8μM for stigmasterol, brassicasterol and ergosterol respectively) similar to the estimated Km for desmosterol (26.3μM). The sterol 5,22-cholestedien-3β-ol, an unusual desmosterol isomer that lacks the alkyl groups characteristic of phytosterols, acted as a much stronger inhibitor of 24-reductase (Ki = 3.34μM). The usually low intracellular concentrations of the physiological substrates of 24-reductase explains the strong inhibition of cholesterol biosynthesis that these compounds exert in cells. Given that inhibition of sterol 24-reductase was achieved at physiologically relevant concentrations, it may represent an additional mechanism for the cholesterol-lowering action of phytosterols, and opens up the possibility of using certain 22-unsaturated sterols as effective hypocholesterolaemic agents.
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August 2002
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Research Article|
August 15 2002
Inhibition of cholesterol biosynthesis by Δ22-unsaturated phytosterols via competitive inhibition of sterol Δ24-reductase in mammalian cells
Carlos FERNÁNDEZ;
Carlos FERNÁNDEZ
∗Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, 28034 Madrid, Spain
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Yajaira SUÁREZ;
Yajaira SUÁREZ
∗Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, 28034 Madrid, Spain
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Antonio J. FERRUELO;
Antonio J. FERRUELO
∗Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, 28034 Madrid, Spain
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Diego GÓMEZ-CORONADO;
Diego GÓMEZ-CORONADO
∗Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, 28034 Madrid, Spain
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Miguel A. LASUNCIÓN
Miguel A. LASUNCIÓN
1
∗Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, 28034 Madrid, Spain
†Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá, 28771 Alcalá de Henares, Spain
1To whom correspondence should be addressed (e-mail miguel.a.lasuncion@hrc.es).
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Publisher: Portland Press Ltd
Received:
December 04 2001
Revision Received:
March 26 2002
Accepted:
April 11 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (1): 109–119.
Article history
Received:
December 04 2001
Revision Received:
March 26 2002
Accepted:
April 11 2002
Citation
Carlos FERNÁNDEZ, Yajaira SUÁREZ, Antonio J. FERRUELO, Diego GÓMEZ-CORONADO, Miguel A. LASUNCIÓN; Inhibition of cholesterol biosynthesis by Δ22-unsaturated phytosterols via competitive inhibition of sterol Δ24-reductase in mammalian cells. Biochem J 15 August 2002; 366 (1): 109–119. doi: https://doi.org/10.1042/bj20011777
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