Key result
Reconstitution of human apoC-III expression in apoc3-null mice resulted in robust production of VLDL(1), demonstrating its central role in lumenal lipid droplet formation and bulk TAG incorporation.
ApoC-III plays a critical intracellular role in promoting the assembly and secretion of atherogenic TAG-rich VLDL1, providing mechanistic insights into its influence on plasma TAG concentrations and premature atherosclerosis.
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ApoC-III may be a therapeutic target to limit VLDL1 secretion; animal data leaves open human translation and clinical benefit.
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 VLDL(1) (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 VLDL(1) production in vivo. Reconstitution of apoC-III expression using adenovirus encoding human apoC-III resulted in robust production of VLDL(1) containing apoB-100 or apoB-48. The stimulatory effect of human apoC-III on the assembly and secretion of VLDL(1) 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 VLDL(1) 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 VLDL(1) assembly. Unraveling the intracellular role of apoC-III in the atherogenic TAG-rich VLDL(1) production provides new insights into the strong influence of the APOA5-A4-C3-A1 gene locus on plasma TAG concentrations and premature atherosclerosis.
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Zemin Yao (2012) studied Lipid metabolism. Human apoC-III expression vs. apoc3-null was evaluated on VLDL(1) production. Reconstitution of human apoC-III expression in apoc3-null mice resulted in robust production of VLDL(1), demonstrating its central role in lumenal lipid droplet formation and bulk TAG incorporation.
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