Title
Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL
Author
TNO Kwaliteit van Leven
Berbée, J.F.P.
van der Hoogt, C.C.
Sundararaman, D.
Havekes, L.M.
Rensen, P.C.N.
Publication year
2005
Abstract
Studies in humans and mice have shown that increased expression of apolipoprotein C-I (apoC-I) results in combined hyperlipidemia with a more pronounced effect on triglycerides (TGs) compared with total cholesterol (TC). The aim of this study was to elucidate the main reason for this effect using human apoC-I-expressing (APOC1) mice. Moderate plasma human apoC-I levels (i.e., 4-fold higher than human levels) caused a 12-fold increase in TG, along with a 2-fold increase in TC, mainly confined to VLDL. Cross-breeding of APOC1 mice on an apoE-deficient background resulted in a marked 55-fold increase in TG, confirming that the apoC-I-induced hyperlipidemia cannot merely be attributed to blockade of apoE-recognizing hepatic lipoprotein receptors. The plasma half-life of [3H]TG-VLDL-mimicking particles was 2-fold increased in APOC1 mice, suggesting that apoC-I reduces the lipolytic conversion of VLDL. Although total postheparin plasma LPL activity was not lower in APOC1 mice compared with controls, apoC-I was able to dose-dependently inhibit the LPL-mediated lipolysis of [3H]TG-VLDL-mimicking particles in vitro with a 60% efficiency compared with the main endogenous LPL inhibitor apoC-III. Finally, purified apoC-I impaired the clearance of [3H]TG-VLDL- mimicking particles independent of apoE-mediated hepatic uptake in lactoferrin-treated mice. Therefore, we conclude that apoC-I is a potent inhibitor of LPL-mediated TG-lipolysis. Chemicals / CAS: tritium, 10028-17-8; Apolipoproteins C; Apolipoproteins E; Apolipoproteins; Lactoferrin; Lipoprotein Lipase, EC 3.1.1.34; Lipoproteins, VLDL; Triglycerides
Subject
Biomedical Research
Apolipoprotein C-I
Fatty acids
Lipid metabolism
Lipoprotein lipase
Triglycerides
Very low density lipoprotein
Lipoprotein receptor
Tritium
Very low density lipoprotein
Animal experiment
Animal model
Cholesterol blood level
Controlled study
Enzyme activity
Half life time
Hyperlipidemia
Hyperlipoproteinemia type 3
Lipolysis
Mouse
Nonhuman
Pathophysiology
Protein expression
Transgenic mouse
Animals
Apolipoproteins
Apolipoproteins C
Apolipoproteins E
Humans
Hypertriglyceridemia
Lactoferrin
Lipoproteins, VLDL
Liver
Mice
Mice, Inbred C57BL
Mice, Transgenic
Phenotype
Time Factors
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DOI
https://doi.org/10.1194/jlr.m400301-jlr200
TNO identifier
238330
ISSN
0022-2275
Source
Journal of Lipid Research, 46 (46), 297-306
Document type
article