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RP2E INRA Université de Lorraine

Communications

Apolipoprotein CIII Sialylation is a Critical Determinant of Liver Triglyceride Metabolism

Arteriosclerosis, Thrombosis and Vascular Biology / Peripheral Vascular Disease Meeting, 07-09 mai, San Francisco, Etats-Unis

Yassine, H.-N., Ramrakhiani, A., Parekh, A., Walker, R., Goran, M., Trenchevska, O., Nedelkov, D., Nelson, R., Koska, J., Reaven, P.-D., Hayden, C.-T., Yen, F.T.

2015

 

Apo CIII inhibits lipoprotein lipase activity and remnant particle uptake in the liver by the lipolysis stimulated receptor (LSR); and therefore modulates liver and systemic lipid metabolism.  Although post-translational modifications of apolipoprotein (apo) CIII lead to asialylated, mono- or disialylated variants, the biological relevance of these sialylations is not known.  Our objective was to determine whether sialylated variants of apo CIII regulate lipoprotein triglyceride metabolism and development of fatty liver. In 223 obese non-diabetic adolescent Hispanic participants, apo CIII variants in plasma were measured using mass spectrometric immunoassay.  Analysis of apo CIII revealed that the increased plasma ratio of di- to mono-sialylated CIII was associated with lower triglyceride levels (r=-0.43, p<0.001), and less liver fat by MRI (r=-0.27, p<0.001) independent of total apo CIII concentrations. Higher plasma concentrations of the mono-sialylated, but not the di-sialylated variant, were associated with higher triglycerides concentrations (r=0.53, p<0.001). Using HepG2 liver cells, we demonstrated that immunoprecipitated apo CIII from VLDL of participants in the upper quartile of di-sialylated to mono-sialylated CIII ratio less effectively inhibited LSR-mediated VLDL uptake compared with CIII isolated from VLDL of participants in the lower quartile of CIII sialylation ratio.  This effect on VLDL uptake was abolished by removal of sialic acid with neuraminidase.  VLDL particles with higher apo CIII sialylation were also enriched with ApoE.  Apo CIII isolated from VLDL of participants in the upper or lower quartile of CIII sialation ratio demonstrated a similar capacity to inhibit fatty acid release by lipoprotein lipase ex vivo.  We conclude that a greater ratio of di-sialylated to mono-sialylated apo CIII together with particle enrichment in apo E allow for more efficient VLDL liver uptake and is associated with less liver fat. The measurement of apo CIII sialylation in plasma may be a useful index of triglyceride metabolism and risk of fatty liver.

 

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