ApoC-III deficiency prevents hyperlipidemia induced by apoE overexpression.
Adenovirus-mediated overexpression of human apolipoprotein E (apoE) induces hyperlipidemia by stimulating the VLDL-triglyceride (TG) production rate and inhibiting the LPL-mediated VLDL-TG hydrolysis rate. Because apoC-III is a strong inhibitor of TG hydrolysis, we questioned whether Apoc3 deficiency might prevent the hyperlipidemia induced by apoE overexpression in vivo. Injection of 2 x 10(9) plaque-forming units of AdAPOE4 caused severe combined hyperlipidemia in Apoe-/- mice [TG from 0.7 +/- 0.2 to 57.2 +/- 6.7 mM; total cholesterol (TC) from 17.4 +/- 3.7 to 29.0 +/- 4.1 mM] that was confined to VLDL/intermediate density lipoprotein-sized lipoproteins. In contrast, Apoc3 deficiency resulted in a gene dose-dependent reduction of the apoE4-associated hyperlipidemia (TG from 57.2 +/- 6.7 mM to 21.2 +/- 18.5 and 1.5 +/- 1.4 mM; TC from 29.0 +/- 4.1 to 16.4 +/- 9.8 and 2.3 +/- 1.8 mM in Apoe-/-, Apoe-/-.Apoc3+/-, and Apoe-/-.Apoc3-/- mice, respectively). In both Apoe-/- mice and Apoe-/-.Apoc3-/- mice, injection of increasing doses of AdAPOE4 resulted in up to a 10-fold increased VLDL-TG production rate. However, Apoc3 deficiency resulted in a significant increase in the uptake of TG-derived fatty acids from VLDL-like emulsion particles by white adipose tissue, indicating enhanced LPL activity. In vitro experiments showed that apoC-III is a more specific inhibitor of LPL activity than is apoE. Thus, Apoc3 deficiency can prevent apoE-induced hyperlipidemia associated with a 10-fold increased hepatic VLDL-TG production rate, most likely by alleviating the apoE-induced inhibition of VLDL-TG hydrolysis.
Gerritsen
Gery
G
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Rensen
Patrick C N
PC
Kypreos
Kyriakos E
KE
Zannis
Vassilis I
VI
Havekes
Louis M
LM
Willems van Dijk
Ko
K
D000818:Animals; D053305:Apolipoprotein C-III; D053327:Apolipoprotein E4; D001056:Apolipoproteins C / Q000172:deficiency*; D001057:Apolipoproteins E / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics / Q000517:prevention & control*; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D014162:Transfection; D014280:Triglycerides / Q000097:blood
D053305:Apolipoprotein C-III; D053327:Apolipoprotein E4; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D008055:Lipids; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D008071:Lipoprotein Lipase