Cholesterol metabolism. Effect of 26-thiacholesterol and 26-aminocholesterol, analogues of 26-hydroxycholesterol, on cholesterol synthesis and low-density-lipoprotein-receptor binding

Abstract

1. The effects of 26-aminocholesterol and 26-thiacholesterol on cholesterol synthesis and LDL (low-density lipoprotein)-receptor activity were compared with naturally occurring 26-hydroxycholesterol utilizing both human fibroblasts and hepatoma (Hep G2) cells. 2. At equimolar concentrations (0.625 microM), down-regulation of LDL-receptor activity and cholesterol synthesis was greater with human fibroblasts than with Hep G2 cells. 3. At much higher concentrations (5-20 microM) the 26-thia analogue had little effect on either cholesterol synthesis or LDL-receptor activity.

Effects of CYP7A1 overexpression on cholesterol and bile acid homeostasis

“…The effect of 7␣-hydroxycholesterol in the regulation of the LDLR is even less clear, with previous effects clearly dependent on oxysterol cellular concentration (29,31). These results suggest a differential effect of 7␣-hydroxycholesterol on HMGR and LDLR regulation.…”

Cholesterol and bile acid synthesis in Hep G2 cells. Metabolic effects of 26- and 7 α-hydroxycholesterol

“…; twice in the same solvent system). 2H2O (99.6 %) was purchased from Merck Stable Isotopes, St. Louis, MO, U.S.A. Hep G2 cells were a gift from Dr. Barbara Knowles of the Wistar Institute, Philadelphia, PA, U.S.A. Materials for maintenance of the cell line in our facility have been described previously [4].…”

27‐Hydroxycholesterol modulation of low density lipoprotein metabolism in cultured human hepatic and extrahepatic cells

“…The shorter periods of incubation with oxysterols required to achieve 50% i~ibition of LDL uptake and degradation could reflect a different rate of diffusion has been recently reported [21] than an analogue of into the cell. In fact cholesterol has to equilibrate with 27-hydroxycholesterol, 26aminocholestero1, that has a large membrane pool (about 90% of total cellular the same polarity of 27-hydroxycholesterol, possesses a cholesterol) and must increase the cellular free cholestsimilar ability in regulating cellular cholesterol homeoerol content before eliciting its effect on the expression stasis.…”

“…On the contrary another analogue, 26&a-of the genes regulating the synthesis of both LDL-recepcholesterol, which is less polar than 27-hytor and HMG-CoA reductase [l]. Moreover, cholestdroxycholesterol and 26-aminocholesterol, is less effecerol is less polar than its oxygenated derivatives and it tive in suppressing the expression of LDL-receptor [21]. These results suggest that sterol polarity could be more important than the presence of an oxygenated function on the molecule.…”

“…These data suggest that the physiological regulator of cholesterol homeostasis is likely to be an oxygenated cholesterol species formed in a cytochrome P,,,-catalyzed reaction. 25-Hydroxycholesterol and 27-hydroxycholesterol are among the most potent inhibitors of the HMO-CoA reductase [ 1 3 and, in addition, they decrease the receptor-mediated uptake and degradation of low density ~~prote~~ in cultured cells [17,[20][21][22], thus interfering with both the endogenous and exo~nous supply of cholesterol to the cells. 2% Hydroxyeholesterol seems to be an autoxidation product of cholesterol and its presence in vivo is disputed .…”