Acute P-407 Administration to Mice Causes Hypercholesterolemia by Inducing Cholesterolgenesis and Down-Regulating Low-Density Lipoprotein Receptor Expression

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.