title: Cholesterol homeostasis is modulated by amphiphiles at transcriptional and post-transcriptional loci.
abstract: A variety of amphiphiles inhibit plasma membrane cholesterol esterification and induce 3-hydroxy-3-methylglutaryl-coenzyme A reductase accumulation in cultured cells; among these are steroids, hydrophobic amines, phenothiazines, ionophores, colchicine, and lysophosphatides. It has been proposed that these amphiphiles signal a sterol deficiency to regulatory sites by blocking the movement of plasma membrane cholesterol into the cell (Lange, Y., and Steck, T. L. 1994. J. Biol. Chem. 269: 29371-29374). If this were the case, these agents also should enhance transcription of sterol responsive genes and stabilize 3-hydroxy-3-methylglutaryl-coenzyme A reductase. As a test of this hypothesis, the effect of the amphiphiles on such transcriptional and post-transcriptional events was assessed. A mouse embryo cell line was transfected with a construct containing the promoter for the human low density lipoprotein receptor upstream of the DNA sequence coding for chloramphenicol acyltransferase (CAT). Incubation of these cells for 7-18 h with the aforementioned agents caused the level of expression of the promoter/CAT construct to increase 2- to 9-fold. We showed further that the amphiphiles stimulated 3-hydroxy-3 methylglutaryl-coenzyme A reductase activity by increasing gene transcription as well as by decreasing degradation of the enzyme. These are the predicted homeostatic responses to cell cholesterol deficiency. These findings support the hypothesis that certain amphiphiles falsely signal a cholesterol deficiency to the intracellular sites regulating cholesterol homeostasis.
authors.affiliation: Department of Pathology, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Lange
authors.forename: H
authors.initials: H
authors.lastname: Duan
authors.forename: T
authors.initials: T
authors.lastname: Mazzone
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D002738:Chloroquine / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism*; D003609:Dactinomycin / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005786:Gene Expression Regulation; D006706:Homeostasis; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008985:Monensin / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D013501:Surface-Active Agents / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D011973:Receptors, LDL; D013501:Surface-Active Agents; D003609:Dactinomycin; D004958:Estradiol; D002738:Chloroquine; D008985:Monensin; D002784:Cholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D015500:Chloramphenicol O-Acetyltransferase