Endogenous apoC-I increases hyperlipidemia in apoE-knockout mice by stimulating VLDL production and inhibiting LPL.
Previous studies have shown that overexpression of human apolipoprotein C-I (apoC-I) results in moderate hypercholesterolemia and severe hypertriglyceridemia in mice in the presence and absence of apoE. We assessed whether physiological endogenous apoC-I levels are sufficient to modulate plasma lipid levels independently of effects of apoE on lipid metabolism by comparing apolipoprotein E gene-deficient/apolipoprotein C-I gene-deficient (apoe-/-apoc1-/-), apoe-/-apoc1+/-, and apoe-/-apoc1+/+ mice. The presence of the apoC-I gene-dose-dependently increased plasma cholesterol (+45%; P < 0.001) and triglycerides (TGs) (+137%; P < 0.001), both specific for VLDL. Whereas apoC-I did not affect intestinal [3H]TG absorption, it increased the production rate of hepatic VLDL-TG (+35%; P < 0.05) and VLDL-[35S]apoB (+39%; P < 0.01). In addition, apoC-I increased the postprandial TG response to an intragastric olive oil load (+120%; P < 0.05) and decreased the uptake of [3H]TG-derived FFAs from intravenously administered VLDL-like emulsion particles by gonadal and perirenal white adipose tissue (WAT) (-34% and -25%, respectively; P < 0.05). As LPL is the main enzyme involved in the clearance of TG-derived FFAs by WAT, and total postheparin plasma LPL levels were unaffected, these data demonstrate that endogenous apoC-I suffices to attenuate the lipolytic activity of LPL. Thus, we conclude that endogenous plasma apoC-I increases VLDL-total cholesterol and VLDL-TG dose-dependently in apoe-/- mice, resulting from increased VLDL particle production and LPL inhibition.
Netherlands Organization for Applied Scientific Research-Quality of Life, Department of Biomedical Research, Gaubius Laboratory, 2301 CE Leiden, The Netherlands. m.westerterp@lumc.nl
Marit
M
Westerterp
Willeke
W
de Haan
Jimmy F P
JF
Berbée
Louis M
LM
Havekes
Patrick C N
PC
Rensen
D000818:Animals; D053302:Apolipoprotein C-I; D001056:Apolipoproteins C / Q000097:blood / Q000235:genetics / Q000502:physiology*; D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics / Q000502:physiology*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D006949:Hyperlipidemias / Q000097:blood / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000032:analysis / Q000096:biosynthesis* / Q000097:blood; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019518:Postprandial Period
D053302:Apolipoprotein C-I; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D008079:Lipoproteins, VLDL; D002784:Cholesterol; D008049:Lipase; D008071:Lipoprotein Lipase