Abstract | OBJECTIVE: APPROACH AND RESULTS:
CSL112 was infused into human subjects in single (57 subjects) and multiple (36 subjects) ascending dose trials. Pharmacokinetic and biomarker assessments were conducted before and after infusions. CSL112 caused an immediate, up to 3-fold elevation of apoA-I and subsequent movement of tissue cholesterol into plasma. Cholesterol appeared first as unesterified cholesterol in the high-density lipoprotein (HDL) fraction and was promptly esterified by lecithin cholesterol acyltransferase. HDL cholesterol increased up to 81±16.5%. Underlying this movement of cholesterol was an immediate and strong rise in the ability of plasma to promote cholesterol efflux from cells ex vivo. CSL112 had its greatest impact on the fraction of efflux mediated by ATP-binding cassette transporter A1 (ABCA1), a cholesterol transporter induced in cholesterol-loaded tissues such as plaque. ABCA1-dependent efflux capacity increased ≤630±421% and total efflux capacity by ≤192±40%. In keeping with this finding, we observed a profound rise in very small HDL, also known as preβ1-HDL, the preferred substrate for ABCA1. Very small HDL increased ≤3596±941%. Elevations in apoA-I, cholesterol efflux, and very small HDL were dose-proportional over a wide range. No significant changes in atherogenic lipids were observed at any dose. CONCLUSIONS:
|
Authors | Andreas Gille, Rachael Easton, Denise D'Andrea, Samuel D Wright, Charles L Shear |
Journal | Arteriosclerosis, thrombosis, and vascular biology
(Arterioscler Thromb Vasc Biol)
Vol. 34
Issue 9
Pg. 2106-14
(Sep 2014)
ISSN: 1524-4636 [Electronic] United States |
PMID | 24969776
(Publication Type: Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
|
Copyright | © 2014 American Heart Association, Inc. |
Chemical References |
- ABCA1 protein, human
- ATP Binding Cassette Transporter 1
- Apolipoprotein A-I
- Biomarkers
- CSL112
- Cholesterol Esters
- Cholesterol, HDL
- Lipoproteins, HDL
- Cholesterol
- Phosphatidylcholine-Sterol O-Acyltransferase
|
Topics |
- ATP Binding Cassette Transporter 1
(blood)
- Adult
- Apolipoprotein A-I
(metabolism)
- Biological Transport
- Biomarkers
- Cholesterol
(blood)
- Cholesterol Esters
(metabolism)
- Cholesterol, HDL
(blood)
- Dose-Response Relationship, Drug
- Female
- Humans
- Infusions, Intravenous
- Lipoproteins, HDL
(administration & dosage, pharmacokinetics, pharmacology)
- Male
- Phosphatidylcholine-Sterol O-Acyltransferase
(metabolism)
- Young Adult
|