Title:Human Apolipoprotein C-III – A New Intrahepatic Protein Factor Promoting Assembly and Secretion of Very Low Density Lipoproteins
Volume: 12
Issue: 2
Author(s): Zemin Yao
Affiliation:
Keywords:
ApoC3, VLDL, hypotriglyceridemia, hyperalphalipoproteinemia, atherosclerosis
Abstract: Apolipoprotein (apo) C-III is a small protein (79 amino acids) and a component of triacylglycerol (TAG)-rich
very low density lipoproteins (VLDL) and high density lipoproteins. We have unraveled a new intracellular role of apoCIII
in promoting hepatic VLDL1 (Sf > 100) assembly/secretion under lipid-rich conditions. Feeding apoc3-null mice with a
high fat diet for two weeks or palm oil gavage failed to stimulate VLDL1 production in vivo. Reconstitution of apoC-III
expression using adenovirus encoding human apoC-III resulted in robust production of VLDL1 containing apoB-100 or
apoB-48. The stimulatory effect of human apoC-III on the assembly and secretion of VLDL1 was recapitulated ex vivo in
McA-RH7777 cells cultured in lipid-rich media. Metabolic labeling experiments showed that apoC-III plays a central role
in (i) the formation of lumenal lipid droplets (LLD) rich in TAG, and (ii) promoting bulk TAG incorporation during
VLDL1 assembly. Structure-function analysis of naturally occurring apoC-III variants (Ala23Thr and Lys58Glu) defined
two functional domains that play respective roles in LLD formation and VLDL1 assembly. Unraveling the intracellular
role of apoC-III in the atherogenic TAG-rich VLDL1 production provides new insights into the strong influence of the
APOA5-A4-C3-A1 gene locus on plasma TAG concentrations and premature atherosclerosis.
