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Acute P-407 administration to mice causes hypercholesterolemia by inducing cholesterolgenesis and down-regulating
Carlos Leon1, Kishor M Wasan, Kristina Sachs-Barrable
1Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Purpose:
Poloxamer 407 (P-407) is a chemical that induces a dose-controlled dyslipidemia in mice. Our aim was to determine the acute effects of P-407 treatment on the mechanisms that influence hepatic cholesterol homeostasis.
Methods:
We measured lipid levels in plasma and liver samples from control and P-407-treated mice (24 h post-i.p. injection of 0.5 g kg(-1) of P-407 or saline for the control mice). We measured acyl-coenzyme A:cholesterol acyltransferase (ACAT) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activities in liver microsomes. The protein expression of ACAT2, scavenger receptor class B, type I (SR-BI), ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G8 (ABCG8), low-density lipoprotein receptor (LDLr), and actin was measured by immunoblot.
Results:
We found an increase in plasma cholesterol and triglyceride levels as well as increased hepatic cholesteryl esters (CE) in P-407-treated mice. The hepatic ACAT microsomal activity and ACAT2 protein expression were not altered by P-407. The protein expression of the LDLr was decreased in the livers of P-407-treated mice. This decrease was specific, because the expression of the SR-BI was unchanged. The P-407-induced hypercholesterolemia was accounted for by increased activity and protein expression of HMG-CoA reductase. ATP-binding cassette transporters A1 and G8 protein expression were not significantly different in P-407-treated mice compared to controls.
Conclusions:
The increased hepatic CE levels, following P-407 treatment, was neither related to an up-regulation of ACAT2 nor enhanced SR-BI expression. Hypercholesterolemia was associated with an up-regulation of both the protein expression and activity of HMG-CoA reductase and decreased LDLr expression.
