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Apolipoprotein E Mimetics and Cholesterol-Lowering Properties

Abstract

Apolipoprotein E (apoE) is a ligand for clearance of lipoprotein remnants such as chylomicrons and very low-density lipoproteins. It has anti-atherogenic and anti-inflammatory properties. Therefore, there is extensive ongoing research to create peptides that can mimic properties of apoE. A number of synthetic peptides that encompass different regions of apoE have been studied for inhibiting inflammatory states, including Alzheimer disease. However, peptides that clear atherogenic lipoproteins, analogous to apoE, via enhanced hepatic uptake have not been previously reviewed. Toward this end, we describe the design and studies of a dual-domain apoE mimetic peptide, Ac-hE18A-NH2. This peptide consists of residues 141–150, the putative receptor-binding region of human apoE, covalently linked to a well characterized class A amphipathic helix, 18A, which has no sequence homology to any other exchangeable apolipoprotein sequences. It demonstrates dramatic effects in reducing plasma cholesterol levels in dyslipidemic mouse and rabbit models. We discuss the scientific rationale and review the literature for the design and efficacy of the peptide. Analogous to apoE, this peptide bypasses the low-density lipoprotein receptor for the hepatic uptake of atherogenic lipoproteins via heparan sulfate proteoglycan (HSPG). ApoE mimetics such as Ac-hE18A-NH2 may therefore restore or replace ligands in genetically induced hyperlipidemias to enable reduction in atherogenic lipoproteins via HSPG even in the absence of functional low-density lipoprotein receptors. Therefore, this and similar peptides may be useful in the treatment of dyslipidemic disorders such as familial hyperlipidemia and atherosclerosis.

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Acknowledgments

This work is supported by the following grants: NIHR01 HL090803 (GMA) and NIH 5K08HL085282 (HG). GMA is a principal in Bruin Pharma and is a stock holder in Lipimetix, which has licensed apoE mimetic technology from UAB Research Foundation. DWG and HG have intellectual property rights to certain cationic peptides. DG is a founder of Lipimetix, LLC, which has licensed the apoE mimetic technology from University of Alabama, Birmingham Research Foundation.

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Correspondence to Dr G. M. Anantharamaiah or Dr Himanshu Gupta.

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Sharifov, O.F., Nayyar, G., Garber, D.W. et al. Apolipoprotein E Mimetics and Cholesterol-Lowering Properties. Am J Cardiovasc Drugs 11, 371–381 (2011). https://doi.org/10.2165/11594190-000000000-00000

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Keywords

  • Plasma Cholesterol Level
  • Fast Protein Liquid Chromatography
  • Atherogenic Lipoprotein
  • Amphipathic Helix
  • Lipoprotein Remnant