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J. Biol. Chem., Vol. 262, Issue 30, 14435-14440, Oct, 1987
SR Panini, A Gupta, RC Sexton, EJ Parish and H Rudney
Treatment of rat intestinal epithelial cells in culture (IEC-6) with
progesterone (10 micrograms/ml) caused a strong inhibition of cholesterol
biosynthesis as indicated by a decreased incorporation of radiolabel from
[3H]acetate. This inhibition was accompanied by an accumulation of
radioactivity in an intermediate which coeluted with authentic desmosterol
upon high performance liquid chromatography (HPLC). In addition, treatment
of cells with progesterone caused lesser accumulation of radiolabel in
products with retention times (RT) of 7.9 and 13.5 min on reverse-phase
HPLC. The RT-13.5 compound was tentatively identified as
cholesta-5,7,24-trien-3 beta-ol based on its relative retention and on its
conversion to cholesterol upon incubation with untreated cells. The RT-7.9
compound was identified as 24 (S),25- epoxycholesterol (S-EC) based on its
coelution with authentic S-EC and by its conversion to
25-hydroxycholesterol upon reduction with LiAlH4. Incubation of IEC-6 cells
with chemically prepared S-EC resulted in dose-dependent suppression of
3-hydroxy-3-methylglutaryl-coenzyme A reductase activity within 6 h (I50 =
0.3 microM). Pretreatment of cells with progesterone prevented this
suppressive effect. No suppression of reductase activity was observed in
progesterone-treated cells in spite of obvious accumulation of S-EC in
amounts sufficient to effect regulation; instead, a 2-3-fold increase in
3-hydroxy-3-methylglutaryl- coenzyme A reductase activity occurred within a
24-h period. Following the removal of progesterone from the culture medium,
reductase activity declined rapidly over the next 6 h. However, IEC-6 cells
could not metabolize S-EC, derived either endogenously or exogenously,
during a similar time frame; nor did progesterone affect the uptake of
exogenous S-EC by IEC-6 cells. These results show that although
progesterone treatment of cultured cells promotes the synthesis of a
natural oxysterol suppressor of 3-hydroxy-3-methyl-glutaryl-coenzyme A
reductase, the continued presence of progesterone prevents the regulatory
action of S-EC. The unique nature of this interference is high-lighted by
the observation that progesterone could not prevent the suppression of
reductase activity by either 25-hydroxycholesterol or mevalonolactone.
Regulation of sterol biosynthesis and of 3-hydroxy-3-methylglutaryl- coenzyme A reductase activity in cultured cells by progesterone
Department of Biochemistry and Molecular Biology, University of Cincinnati, College of Medicine, Ohio 45267-0522.
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