Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL
article
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
Topics
Biomedical ResearchApolipoprotein C-IFatty acidsLipid metabolismLipoprotein lipaseTriglyceridesVery low density lipoproteinLipoprotein receptorTritiumVery low density lipoproteinAnimal experimentAnimal modelCholesterol blood levelControlled studyEnzyme activityHalf life timeHyperlipidemiaHyperlipoproteinemia type 3LipolysisMouseNonhumanPathophysiologyProtein expressionTransgenic mouseAnimalsApolipoproteinsApolipoproteins CApolipoproteins EHumansHypertriglyceridemiaLactoferrinLipoproteins, VLDLLiverMiceMice, Inbred C57BLMice, TransgenicPhenotypeTime Factors
TNO Identifier
238330
ISSN
00222275
Source
Journal of Lipid Research, 46(2), pp. 297-306.
Pages
297-306