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Mechanism of lipid lowering in mice expressing human apolipoprotein A5

  • Author(s): Fruchart-Najib, Jamila
  • Bauge, Eric
  • Niculescu, Loredan-Stefan
  • Pham, Tatiana
  • Thomas, Benoit
  • Rommens, Corinne
  • Majd, Zouher
  • Brewer, Bryan
  • Rubin, Edward M.
  • Pennacchio, Len A.
  • Fruchart, Jean-Charles
  • et al.
Abstract

Recently, we reported that apoAV plays key role in triglycerides lowering. Here, we attempted to determine the mechanism underlying this hypotriglyceridemic effect. We showed that triglyceride turnover is faster in hAPOA5 transgenic compared to wild type mice. Moreover, both apoB and apoCIII are decreased and LPL activity is increased in postheparin plasma of hAPOA5 transgenic mice. These data suggest a decrease in size and number of VLDL. To further investigate the mechanism of hAPOA5 in hyperlipidemic background, we intercrossed hAPOA5 and hAPOC3 transgenic mice. The effect resulted in a marked decreased of VLDL triglyceride, cholesterol, apolipoproteins B and CIII. In postprandial state, the triglyceride response is abolished in hAPOA5 transgenic mice. We demonstrated that in response to the fat load in hAPOA5XhAPOC3 mice, apoAV shifted from HDL to VLDL, probably to limite the elevation of triglycecrides. In vitro, apoAV activates lipoprotein lipase. However, apoAV does not interact with LPL but interacts physically with apoCIII. This interaction does not seem to displace apoCIII from VLDL but may induce conformational change in apoCIII and consequently change in its function leading the activation of lipoprotein lipase.

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