A dual apolipoprotein C-II mimetic-apolipoprotein C-III antagonist peptide lowers plasma triglycerides.
Animals
Apolipoprotein C-II
/ agonists
Apolipoprotein C-III
/ antagonists & inhibitors
Disease Models, Animal
Female
Half-Life
Humans
Hypertriglyceridemia
/ blood
Lipolysis
Lipoprotein Lipase
/ metabolism
Male
Mice, Inbred C57BL
Molecular Dynamics Simulation
Peptides
/ chemistry
Primates
Triglycerides
/ blood
Journal
Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086
Informations de publication
Date de publication:
29 01 2020
29 01 2020
Historique:
received:
25
01
2019
accepted:
06
12
2019
entrez:
31
1
2020
pubmed:
31
1
2020
medline:
26
9
2020
Statut:
ppublish
Résumé
Recent genetic studies have established that hypertriglyceridemia (HTG) is causally related to cardiovascular disease, making it an active area for drug development. We describe a strategy for lowering triglycerides (TGs) with an apolipoprotein C-II (apoC-II) mimetic peptide called D6PV that activates lipoprotein lipase (LPL), the main plasma TG-hydrolyzing enzyme, and antagonizes the TG-raising effect of apoC-III. The design of D6PV was motivated by a combination of all-atom molecular dynamics simulation of apoC-II on the Anton 2 supercomputer, structural prediction programs, and biophysical techniques. Efficacy of D6PV was assessed ex vivo in human HTG plasma and was found to be more potent than full-length apoC-II in activating LPL. D6PV markedly lowered TG by more than 80% within a few hours in both apoC-II-deficient mice and h
Identifiants
pubmed: 31996466
pii: 12/528/eaaw7905
doi: 10.1126/scitranslmed.aaw7905
pmc: PMC8359806
mid: NIHMS1727423
pii:
doi:
Substances chimiques
Apolipoprotein C-II
0
Apolipoprotein C-III
0
Peptides
0
Triglycerides
0
Lipoprotein Lipase
EC 3.1.1.34
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL045095
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL125654
Pays : United States
Organisme : NHLBI NIH HHS
ID : R37 HL045095
Pays : United States
Organisme : Intramural NIH HHS
ID : Z99 HL999999
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM116961
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL073029
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Références
J Am Heart Assoc. 2018 Aug 7;7(15):e008740
pubmed: 30371242
Nat Med. 2017 Sep;23(9):1086-1094
pubmed: 28825717
Biochemistry. 2001 May 8;40(18):5414-21
pubmed: 11331005
J Comput Chem. 2009 Jul 30;30(10):1545-614
pubmed: 19444816
Atherosclerosis. 2017 Dec;267:49-60
pubmed: 29100061
J Atheroscler Thromb. 2012;19(1):1-12
pubmed: 22129523
J Chem Phys. 2013 Oct 28;139(16):164106
pubmed: 24182003
J Lipid Res. 1983 Jan;24(1):60-71
pubmed: 6403641
J Phys Chem B. 2013 Sep 5;117(35):10183-92
pubmed: 23924441
Am J Physiol Endocrinol Metab. 2006 Oct;291(4):E755-60
pubmed: 16684851
Endocr Rev. 2015 Feb;36(1):131-47
pubmed: 25554923
Science. 2008 Dec 12;322(5908):1702-5
pubmed: 19074352
Arterioscler Thromb Vasc Biol. 2019 Mar;39(3):349-359
pubmed: 30676072
J Biol Chem. 1985 Aug 25;260(18):10248-55
pubmed: 4019510
J Lipid Res. 2015 Jul;56(7):1296-307
pubmed: 25954050
Arterioscler Thromb Vasc Biol. 1997 Aug;17(8):1545-9
pubmed: 9301634
Curr Opin Lipidol. 2015 Feb;26(1):56-63
pubmed: 25551803
Arterioscler Thromb Vasc Biol. 2005 Jul;25(7):1325-31
pubmed: 15831812
J Am Coll Cardiol. 2017 Feb 21;69(7):789-800
pubmed: 28209220
J Lipid Res. 2017 Jul;58(7):1315-1324
pubmed: 28392500
Biochemistry. 2004 Jun 29;43(25):8084-93
pubmed: 15209504
J Pharmacol Exp Ther. 2016 Feb;356(2):341-53
pubmed: 26574515
Circ Res. 2016 Feb 19;118(4):547-63
pubmed: 26892957
N Engl J Med. 2015 Jul 30;373(5):438-47
pubmed: 26222559
J Pharmacol Exp Ther. 2010 Aug;334(2):634-41
pubmed: 20484557
Curr Opin Endocrinol Diabetes Obes. 2015 Apr;22(2):119-25
pubmed: 25692924
J Biol Chem. 1985 Aug 25;260(18):10256-62
pubmed: 4019511
J Nutr Metab. 2019 Feb 3;2019:7078241
pubmed: 30863636
Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1838-43
pubmed: 18658047
Science. 1990 Aug 17;249(4970):790-3
pubmed: 2167514
Science. 1997 Jan 17;275(5298):391-4
pubmed: 8994037
Diabet Med. 2009 Jul;26(7):736-9
pubmed: 19573124
N Engl J Med. 2014 Dec 4;371(23):2200-6
pubmed: 25470695
Circ Res. 2013 May 24;112(11):1479-90
pubmed: 23542898
Curr Cardiovasc Risk Rep. 2010;4(1):1-8
pubmed: 20625533
J Biol Chem. 2002 Feb 8;277(6):4334-42
pubmed: 11719505
Clin Chim Acta. 1982 May 6;121(1):59-65
pubmed: 7083594
Lipids Health Dis. 2017 Dec 06;16(1):233
pubmed: 29212549
J Clin Invest. 2016 Aug 1;126(8):2855-66
pubmed: 27400128
PLoS Comput Biol. 2008 Nov;4(11):e1000231
pubmed: 19023401
Biochem Biophys Res Commun. 1972 Jan 31;46(2):375-82
pubmed: 5057882
Biochemistry. 2014 May 27;53(20):3261-3
pubmed: 24804986
Biochim Biophys Acta. 1979 Jun 21;573(3):501-9
pubmed: 465517
J Phys Chem B. 2010 Jun 17;114(23):7830-43
pubmed: 20496934
J Pharmacol Exp Ther. 2015 Feb;352(2):227-35
pubmed: 25395590
J Chem Theory Comput. 2012 Sep 11;8(9):3257-3273
pubmed: 23341755
J Biol Chem. 2015 Jul 17;290(29):18029-18044
pubmed: 26026161
Nat Genet. 2018 Nov;50(11):1514-1523
pubmed: 30275531
Biochim Biophys Acta Biomembr. 2017 Feb;1859(2):135-145
pubmed: 27814978
Nucleic Acids Res. 2018 Jul 2;46(W1):W315-W322
pubmed: 29893907
J Lipid Res. 1992 Feb;33(2):141-66
pubmed: 1569369