ApoCIII deficiency prevents hyperlipidemia induced by apoE overexpression

Gery Gerritsen, Patrick C. N. Rensen, Kyriakos E. Kypreos, Vassilis I. Zannis, Louis M. Havekes, and Ko Willems van Dijk

General Internal Medicine and Human Genetics, Leiden University Medical Center, Leiden 2333AL

Corresponding Author: kowvd{at}lumc.nl

Adenovirus-mediated overexpression of human apoE induces hyperlipidemia by stimulating the VLDL-TG production rate and inhibiting the LPL-mediated VLDL-TG hydrolysis rate. Since apoCIII is a strong inhibitor of TG hydrolysis, we questioned whether Apoc3-deficiency might prevent the hyperlipidemia induced by apoE overexpression in vivo. Injection of 2x109 pfu AdAPOE4 caused severe combined hyperlipidemia in Apoe-/- mice (TG from 0.7±0.2 to 57.2±6.7 mM; TC from 17.4±3.7 to 29.0±4.1 mM) that was confined to VLDL/IDL 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 an up to 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 apoCIII is a more specific inhibitor of LPL-activity than 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.

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