Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL.
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.
Berbée
Jimmy F P
JF
Netherlands Organization for Applied Scientific Research-Prevention and Health, Gaubius Laboratory, 2301 CE Leiden, The Netherlands. jfp.berbee@pg.tno.nl
van der Hoogt
Caroline C
CC
Sundararaman
Deepa
D
Havekes
Louis M
LM
Rensen
Patrick C N
PC
D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism; D001056:Apolipoproteins C / Q000235:genetics*; D001057:Apolipoproteins E / Q000378:metabolism; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics* / Q000378:metabolism*; D066298:In Vitro Techniques; D007781:Lactoferrin / Q000494:pharmacology; D050356:Lipid Metabolism; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D001053:Apolipoproteins; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D008071:Lipoprotein Lipase; D007781:Lactoferrin