Regulation of low density lipoprotein metabolism by 26‐hydroxycholesterol in human fibroblasts

Abstract

Oxygenated derivatives of cholesterol are believed to play a role in cellular cholesterol homeostasis through the feed-back control of its biosynthesis. We report that 26-hydroxycholesterol inhibits the specific binding, uptake and degradation of t25I-LDL in human fibroblasts. The effect is dose-dependent, and saturation kinetics indicates a reduction of LDL-binding sites with no effect on iigand affinity. The results support a possible role of 26-hydroxycholesterol, a physiological oxysterol, in the regulation of cellular cholesterol homeostasis.26-Hydroxycholesterol; Oxysterol; LDL; LDL receptor; (Human fibroblast)

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

“…The findings in the present study together with a recent report that 26-hydroxycholesterol down-regulates LDLreceptor activity in fibroblasts [22] are consonant with studies of the promoter region of the genes regulating both LDL receptor and HMG-CoA reductase synthesis [23]. It has been shown that sterol-dependent repression of both these genes resides in their promoter regions, segments of which have a similar nucleotide sequence.…”

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.…”

Failure of vitamin E to protect cultured human arterial smooth muscle cells against oxysterol-induced cytotoxicity.

“…We found that 260HC reduced significantly the cholesterol content in the membrane. The reduction may result from the inhibiting effect of oxysterols on LDL binding by diminishing the number of LDL binding sites [11] and on cholesterol synthesis by HMG-CoA reductase [8,9]. A decrease in choles terol in the membrane may induce an accumulation of intra cellular calcium by increasing membrane permeability to ions [34] resulting in cell death.…”

“…These oxysterols are involved in the atheroscle rotic process [4,5] and in the severity of the disease [6,7]. They can inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity [8,9], activate acyl Co-A acyltransferase [10] and inhibit low density lipoprotein (LDL) binding by decreasing the number of LDL binding sites [11]. The reduced vascular endothelial cell monolayer barrier function by oxysterols indicated their cytotoxicity in endothelial cells [12,13].…”