Regulation of cholesterol biosynthesis and metabolismin Hep G2 cells by δ8(14)-15-ketoergostane derivatives

   
Mehtiev A.R.1 , Fedchenko V.I.1 , Tkachev Ya.V.2, Timofeev V.P.2, Misharin A.Yu.1

1. V.N. Orekhovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences
2. V.A. Engelghardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
Section: Experimental/Clinical Study
DOI: 10.18097/pbmc20105605576      PubMed Id: 21254628
Year: 2010  Volume: 56  Issue: 5  Pages: 576-586
The comparative study of effects of 5α-cholest-8(14)-en-15-on-3β-ol (I), (22E)-5α-ergosta-8(14),22-dien-15-on-3β-ol (II), (22S,23S)-22,23-oxido-5α-ergost-8(14)-en-15-on-3β-ol (III) and (22R,23R)-22,23-oxido-5α-ergost-8(14)-en-15-on-3β-ol (IV) on HMG-CoA reductase, CYP27A1 and CYP3A4 genes expression in Hep G2 cells was performed. In the contrast to 15-ketocholestane derivative (I), 15-ketoergostane derivatives (II - IV) decreased the HMG- CoA reductase mRNA level; (22R,23R)-22,23-oxido-5α-ergost-8(14)-en-15-on-3β-ol (IV) significantly increased CYP3A4 mRNA level (320% from control). Ketosterol (II) was found to be a more potent inhibitor of cholesterol biosynthesis in Hep G2 cells at a prolong incubation, compared with ketosterol (I). The side chain conformation of compounds (I) - (IV) was evaluated by computational modeling; the correlation between biological activity of these compounds and conformational flexibility of their side chains was found. The results obtained indicated that Δ8(14)-15-ketoergostane derivatives may be used as a sterol biosynthesis and metabolism regulators in liver cells.
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Keywords: oxysterols, cholesterol, biosynthesis, regulation, Hep G2 cells, side chain conformation
Citation:

Mehtiev, A. R., Fedchenko, V. I., Tkachev, Ya. V., Timofeev, V. P., Misharin, A. Yu. (2010). Regulation of cholesterol biosynthesis and metabolismin Hep G2 cells by δ8(14)-15-ketoergostane derivatives. Biomeditsinskaya khimiya, 56(5), 576-586.
This paper is also available as the English translation: 10.1134/S1990750810030066
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