title: 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-NH(2). 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-NH(2) 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.
authors.affiliation: Departments of Medicine, Biochemistry and Molecular Genetics and the Atherosclerosis Research Unit, University of Alabama at Birmingham, USA.
authors.forename: Oleg F
authors.initials: OF
authors.lastname: Sharifov
authors.forename: Gaurav
authors.initials: G
authors.lastname: Nayyar
authors.forename: David W
authors.initials: DW
authors.lastname: Garber
authors.forename: Shaila P
authors.initials: SP
authors.lastname: Handattu
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Mishra
authors.forename: Dennis
authors.initials: D
authors.lastname: Goldberg
authors.forename: G M
authors.initials: GM
authors.lastname: Anantharamaiah
authors.forename: Himanshu
authors.initials: H
authors.lastname: Gupta
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood*; D004195:Disease Models, Animal; D015195:Drug Design; D050171:Dyslipidemias / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D008074:Lipoproteins / Q000494:pharmacology*; D051379:Mice; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D011817:Rabbits; D011973:Receptors, LDL / Q000378:metabolism
chemical_list: C478448:Ac-hE18A-NH(2); D001057:Apolipoproteins E; D008074:Lipoproteins; D010446:Peptide Fragments; D010455:Peptides; D011973:Receptors, LDL; D002784:Cholesterol