Abstract 30: Apolipoprotein CIII Sialylation is a Critical Determinant of Liver Triglyceride Metabolism

Abstract

Apolipoprotein (apo) CIII inhibits lipoprotein lipase (LPL) 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 apo CIII lead to asialylated, mono- or di-sialylated variants, the biological relevance of these sialylations is not known. Our objectives were to determine the association of apo C-III sialylation with plasma triglycerides and liver fat content in vivo, and to evaluate the effect of apo CIII sialylation on lipid uptake in liver cells or LPL activity in vitro. In 209 obese non-diabetic adolescent Hispanic participants, apo CIII variants in plasma were measured using mass spectrometric immunoassay. Increased plasma apo C-III sialylation (di- to mono-sialylated apo CIII ratio) was associated with lower triglyceride levels (r=-0.43, p<0.001) and liver fat (by MRI, r=-0.27, p<0.001) independent of total apo CIII concentrations. Higher plasma concentrations of the mono-, but not the di-sialylated variant, were associated with higher triglycerides concentrations (r=0.53, p<0.001). In HepG2 liver cells, immunoprecipitated apo CIII from VLDL of participants in the upper quartile of plasma apo CIII sialylation less effectively inhibited LSR-mediated VLDL uptake compared to apo CIII from those in the lower quartile of apo CIII sialylation (28% difference, p=0.02). This difference in inhibition was abolished by removal of sialic acid with neuraminidase. Apo CIII isolated from VLDL of participants with different level of apo CIII sialylation showed similar capacity to inhibit fatty acid release by LPL of control VLDL. VLDL particles with higher apo CIII sialylation also demonstrated a two-fold increase in ApoE. We conclude that a greater apo CIII sialylation together with particle enrichment in apo E allow for more efficient VLDL liver uptake and less liver fat accumulation. The measurement of plasma apo CIII sialylation may be a useful index of triglyceride metabolism and risk of fatty liver.