Poloxamer 407-mediated alterations in the activities of enzymes regulating lipid metabolism in rats.
OBJECTIVE
Recently, the P-407-treated mouse was established as a useful animal model of hyperlipidemia and atherosclerosis. The present study was aimed to determine whether P-407-induced hyperlipidemia in the rat is associated with alterations in the activities of enzymes responsible for lipid metabolism.


RESULTS
Rats were made hyperlipidemic by i.p. injection of 1.0 g/kg P-407 and blood samples collected 24 h after administration of P-407. Plasma from P-407-treated rats demonstrated 7- and 13-fold increases in cholesterol and triglycerides, respectively (p < 0.001). The plasma lecithin cholesterol acyl transferase (LCAT) activity in these animals was 4-5-fold greater than control animals (p < 0.05). Further, the plasma cholesteryl ester transfer protein (CETP) activity in P-407-treated rats was increased by approximately 25%, which was inhibited by > 50% in the presence of TP2, a monoclonal anti-CETP antibody (27.03 +/- 3.16 vs. 10.87 +/- 3.23; p < 0.05). The plasma CETP protein levels were also increased by 5-6-fold in P-407-treated animals (control 0.35 +/- 0.17 vs. P-407 treated 1.87 +/- 0.35 ug/ml, p < 0.05). However, the plasma hepatic lipase (HL) (control 49.2 +/- 3.1 vs. P-407-treated 2.0 +/- 0.38 umol/ml/h; p < 0.001) and lipoprotein lipase (LPL) (control 45.9 +/- 0.09 vs. P-407-treated 2.03 +/- 0.38 mol/ml/hr; p<0.001) activities in these animals were significantly inhibited.


CONCLUSIONS
In summary, P-407-induced hyperlipidemia in rats is associated with alterations in plasma LCAT, CETP, HL and LPL activities.
Wasan
Kishor M
KM
Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada. kwasan@interchange.ubc.ca
Subramanian
Ramaswamy
R
Kwong
Mona
M
Goldberg
Ira J
IJ
Wright
Thamrah
T
Johnston
Thomas P
TP
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins; D005079:Excipients / Q000009:adverse effects / Q000494:pharmacology; D006023:Glycoproteins; D006949:Hyperlipidemias / Q000139:chemically induced / Q000201:enzymology*; D008049:Lipase / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008297:Male; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000378:metabolism*; D020442:Poloxamer / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D005079:Excipients; D006023:Glycoproteins; D008055:Lipids; D020442:Poloxamer; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D008049:Lipase; D008071:Lipoprotein Lipase