Some individuals remain at high risk for developing cardiovascular disease even after preventative treatment with cholesterol-lowering medications. This persistent risk has been linked to triglyceride levels, which can remain elevated in spite of substantially lowered LDL, the form of cholesterol associated with heart disease.
Triglyceride concentrations are highly correlated to levels of apolipoprotein C-III (ApoC-III), suggesting that ApoC-III may be a potential target for controlling triglyceride levels. A team led by researchers determined that ApoC-III increases triglyceride levels in blood by interacting with the same pathways that control LDL cholesterol levels.
They found that treating mice with an inhibitor of ApoC-III reduced triglyceride levels, but this effect was prevented in mice lacking two key components of the LDL cholesterol signaling pathway.
ApoC-III antisense oligonucleotide (ASO) treatment lowered plasma TGs in mice lacking lipoprotein lipase (LPL), hepatic heparan sulfate proteoglycan (HSPG) receptors, LDLR, or LRP1 and in animals with combined deletion of the genes encoding HSPG receptors and LDLRs or LRP1. However, the ApoC-III ASO did not lower TG levels in mice lacking both LDLR and LRP1.
LDLR and LRP1 were also required for ApoC-III ASO–induced reduction of plasma TGs in mice fed a high-fat diet, in postprandial clearance studies, and when ApoC-III–rich or ApoC-III–depleted lipoproteins were injected into mice. ASO reduction of ApoC-III had no effect on VLDL secretion, heparin-induced TG reduction, or uptake of lipids into heart and skeletal muscle.
The data indicate that ApoC-III inhibits turnover of TG-rich lipoproteins primarily through a hepatic clearance mechanism mediated by the LDLR/LRP1 axis.
http://www.jci.org/articles/view/86610?key=715136dcf9c20a899b3e
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