Poloxamer 407 (P-407)-mediated reduction in the gene expression of ATP-binding-cassette transporter A1 may contribute to increased cholesterol in peripheral tissues of P-407-treated rats.
The purpose of this study was to determine whether poloxamer 407, a chemical known to increase plasma lipid levels in rodents following parenteral administration, decreased the gene expression of ATP-binding-cassette transporter A1. Using human macrophages cultured with poloxamer 407, there was a significant reduction in the gene expression of ATP-binding-cassette transporter A1; however, there was no effect on the gene expression of either fatty acid synthase or sterol regulatory element binding protein-1. Reduction of ATP-binding-cassette transporter A1 mRNA levels was also observed in both liver and intestine of poloxamer 407-treated rats. When macrophages were cultured with poloxamer 407, the percent of cholesterol effluxed decreased in a concentration-dependent fashion, both in the absence and presence of a synthetic liver X receptor agonist. Lastly, total and unesterified (free) cholesterol concentrations were determined in the liver and 9 peripheral tissues of poloxamer 407- and saline-injected (control) rats. In every tissue, the concentration of total cholesterol for poloxamer 407-treated rats was significantly greater than the corresponding value for controls. Our findings would seem to suggest that the poloxamer 407-mediated reduction in both ATP-binding-cassette transporter A1 gene expression and cellular cholesterol efflux may potentially be one factor that contributes to the accumulation of cholesterol and cholesteryl esters in the liver and 9 peripheral tissues of poloxamer 407-treated rats. Furthermore, the surprising specificity by poloxamer 407 for inhibition of ATP-binding-cassette transporter A1 gene expression over fatty acid synthase and sterol regulatory element binding protein-1 may potentially be due to either disruption of a transcriptional cofactor required for ATP-binding-cassette transporter A1 gene expression, or enhanced turnover of ATP-binding-cassette transporter A1 mRNA.
Johnston
Thomas P
TP
Division of Pharmaceutical Science, Rm. 211A, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, Kansas City, Missouri 64110-2499, United States. johnstont@umkc.edu
Jaye
Michael
M
Webb
Christine L
CL
Krawiec
John A
JA
Alom-Ruiz
Sara Pilar
SP
Sachs-Barrable
Kristina
K
Wasan
Kishor M
KM
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D064429:Fatty Acid Synthases / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008055:Lipids / Q000032:analysis / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020442:Poloxamer / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D013501:Surface-Active Agents / Q000494:pharmacology
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008055:Lipids; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D013501:Surface-Active Agents; D020442:Poloxamer; D002784:Cholesterol; D064429:Fatty Acid Synthases