Overexpression of apoC-I in apoE-null mice: severe hypertriglyceridemia due to inhibition of hepatic lipase.
Apolipoprotein C-I (apoC-I) has been proposed to act primarily via interference with apoE-mediated lipoprotein uptake. To define actions of apoC-I that are independent of apoE, we crossed a moderately overexpressing human apoC-I transgenic, which possesses a minimal phenotype in the WT background, with the apoE-null mouse. Surprisingly, apoE-null/C-I mice showed much more severe hyperlipidemia than apoE-null littermates in both the fasting and non-fasting states, with an almost doubling of cholesterol, primarily in IDL+LDL, and a marked increase in triglycerides; 3-fold in females to 260 +/- 80 mg/dl and 14-fold in males to 1409 +/- 594 mg/dl. HDL lipids were not significantly altered but HDL were apoC-I-enriched and apoA-II-depleted. Production rates of VLDL triglyceride were unchanged as was the clearance of post-lipolysis remnant particles. Plasma post-heparin hepatic lipase and lipoprotein lipase levels were undiminished as was the in vitro hydrolysis of apoC-I transgenic VLDL. However, HDL from apoC-I transgenic mice had a marked inhibitory effect on hepatic lipase activity, as did purified apoC-I. LPL activity was minimally affected. Atherosclerosis assay revealed significantly increased atherosclerosis in apoE-null/C-I mice assessed via the en face assay. Inhibition of hepatic lipase may be an important mechanism of the decrease in lipoprotein clearance mediated by apoC-I.
Conde-Knape
Karin
K
Department of Medicine, Columbia University, 630 W. 168th Street, New York, NY, USA.
Bensadoun
André
A
Sobel
Joan H
JH
Cohn
Jeffrey S
JS
Shachter
Neil S
NS
D000818:Animals; D053302:Apolipoprotein C-I; D001056:Apolipoproteins C / Q000096:biosynthesis / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D001161:Arteriosclerosis; D015243:Cholesterol, VLDL / Q000097:blood / Q000378:metabolism; D006801:Humans; D015228:Hypertriglyceridemia / Q000201:enzymology / Q000235:genetics*; D008049:Lipase / Q000037:antagonists & inhibitors*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D053302:Apolipoprotein C-I; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D015243:Cholesterol, VLDL; D008055:Lipids; D008049:Lipase