Regulation of Glycerophospholipid and Cholesterol Synthesis in Cells by Hydroxylated Cholesterols (Oxysterols)

Abstract

Phosphatidylethanolamine (PE) and cholesterol are major lipid components of mammalian cell membranes. The rate limiting enzymes for the synthesis of PE and cholesterol are CTP: phosphoethanolamine cytidylyltransferase (Pcyt2) and 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), respectively. The transcription and activity of these enzymes in NIH3T3 cells are suppressed by fetal bovine serum (FBS) and hydroxylated cholesterol (oxysterols) in similar dose-dependent manners. These results suggested that the intrinsic oxysterol concentration in cells is important for maintaining membrane lipid components, leading us to investigate the regulation of oxysterol-producing enzyme activity in cells. Using NIH3T3 cells, we found that of all oxysterol-producing enzymes, only the 24S-hydroxycholesterol producing enzyme cytochrome P450 46A1 (Cyp46A1) is expressed. Transcription of Cyp46A1 is suppressed by FBS, and we identified insulin-like growth factor II (IGF-II) in FBS as the factor suppressing Cyp46A1 transcription. The oxysterol level in NIH3T3 cells is also suppressed by IGF-II. These results suggested that the classical hormone IGF-II regulates the oxysterol content in cells and transduces cellular signals.