Hepatic lipid accumulation in apolipoprotein C-I-deficient mice is potentiated by cholesteryl ester transfer protein.
The impact of apolipoprotein C-I (apoC-I) deficiency on hepatic lipid metabolism was addressed in mice in the presence or the absence of cholesteryl ester transfer protein (CETP). In addition to the expected moderate reduction in plasma cholesterol levels, apoCIKO mice showed significant increases in the hepatic content of cholesteryl esters (+58%) and triglycerides (+118%) and in biliary cholesterol concentration (+35%) as compared with wild-type mice. In the presence of CETP, hepatic alterations resulting from apoC-I deficiency were enforced, with up to 58% and 302% increases in hepatic levels of cholesteryl esters and triglycerides in CETPTg/apoCIKO mice versus CETPTg mice, respectively. Biliary levels of cholesterol, phospholipids, and bile acids were increased by 88, 77, and 20%, respectively, whereas total cholesterol, HDL cholesterol, and triglyceride concentrations in plasma were further reduced in CETPTg/apoCIKO mice versus CETPTg mice. Finally, apoC-I deficiency was not associated with altered VLDL production rate. In line with the previously recognized inhibition of lipoprotein clearance by apoC-I, apoC-I deficiency led to decreased plasma lipid concentration, hepatic lipid accumulation, and increased biliary excretion of cholesterol. The effect was even greater when the alternate reverse cholesterol transport pathway via VLDL/LDL was boosted in the presence of CETP.
Gautier
Thomas
T
Center for Liver, Digestive, and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. t.gautier@med.umcg.nl
Tietge
Uwe J F
UJ
Boverhof
Renze
R
Perton
Frank G
FG
Le Guern
Naig
N
Masson
David
D
Rensen
Patrick C N
PC
Havekes
Louis M
LM
Lagrost
Laurent
L
Kuipers
Folkert
F
D000818:Animals; D053302:Apolipoprotein C-I / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D053480:Cholesterol Ester Transfer Proteins / Q000378:metabolism*; D005704:Gallbladder / Q000378:metabolism; D008055:Lipids / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification
D053302:Apolipoprotein C-I; D053480:Cholesterol Ester Transfer Proteins; D008055:Lipids; D012313:RNA