Why Is Apolipoprotein CIII Emerging as a Novel Therapeutic Target to Reduce the Burden of Cardiovascular Disease? - PubMed (original) (raw)
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Why Is Apolipoprotein CIII Emerging as a Novel Therapeutic Target to Reduce the Burden of Cardiovascular Disease?
Marja-Riitta Taskinen et al. Curr Atheroscler Rep. 2016 Oct.
Abstract
ApoC-III was discovered almost 50 years ago, but for many years, it did not attract much attention. However, as epidemiological and Mendelian randomization studies have associated apoC-III with low levels of triglycerides and decreased incidence of cardiovascular disease (CVD), it has emerged as a novel and potentially powerful therapeutic approach to managing dyslipidemia and CVD risk. The atherogenicity of apoC-III has been attributed to both direct lipoprotein lipase-mediated mechanisms and indirect mechanisms, such as promoting secretion of triglyceride-rich lipoproteins (TRLs), provoking proinflammatory responses in vascular cells and impairing LPL-independent hepatic clearance of TRL remnants. Encouraging results from clinical trials using antisense oligonucleotide, which selectively inhibits apoC-III, indicate that modulating apoC-III may be a potent therapeutic approach to managing dyslipidemia and cardiovascular disease risk.
Keywords: CVD; Lipoproteins; Remnants; Triglycerides; apoC-III.
Conflict of interest statement
Compliance with Ethical StandardsConflict of InterestMarja-Riitta Taskinen declares personal fees from Amgen, AstraZeneca, and Chiesi Pharma, grant support and personal fees from Sanofi Aventis and Novo Nordisk, and grant support from Merck Sharp & Dohme.Jan Borén declares grant support and personal fees from AstraZeneca, Sanofi-Aventis, NovoNordisk, and Amgen and personal fees from Merck Sharp & Dome.Human and Animal Rights and Informed ConsentThis article does not contain any studies with human or animal subjects performed by any of the authors.
Figures
Fig. 1
Proatherogenic action of apoC-III on lipid metabolism and atherogenicity. ApoC-III exerts strong atherogenic functions through both indirect and direct mechanisms. These include inducing oversecretion of apoC-III-containing triglyceride-rich lipoproteins (TRLs). These lipoproteins accumulate in the circulation by three mechanisms: (1) impaired lipolysis of large TRLs to smaller remnant particles, (2) impaired LPL-mediated lipolysis of TRLs on capillaries, and (3) impaired LPL-independent and LPL-dependent hepatic clearance of TRL remnants. In addition, apoC-III promotes proinflammatory responses in endothelial cells and monocytes and increases the binding affinity of LDL, leading to increased accumulation of atherogenic lipoproteins in the artery wall
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References
- Brown WV, Levy RI, Fredrickson DS. Studies of the proteins in human plasma very low density lipoproteins. J Biol Chem. 1969;244(20):5687–94. - PubMed
- Windler E, Havel RJ. Inhibitory effects of C apolipoproteins from rats and humans on the uptake of triglyceride-rich lipoproteins and their remnants by the perfused rat liver. J Lipid Res. 1985;26(5):556–65. - PubMed
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