title: Reconstituted HDL elicits marked changes in plasma lipids following single-dose injection in C57Bl/6 mice.
abstract: High-density lipoprotein (HDL)-targeting therapies, including reconstituted HDL (rHDL), are attractive agents for treating dyslipidemia and atherosclerosis, as they may increase HDL levels and enhance therapeutic activities associated with HDL, including reverse cholesterol transport (RCT). Using CSL-111, a rHDL consisting of native human apolipoprotein AI (hApoAI) and phospholipids, we characterized the acute effects of rHDL administration in C57Bl/6 mice to (i) further our understanding of the mechanism of action of rHDL, and (ii) evaluate the usefulness of the mouse as a preclinical model for HDL-targeting therapies. After a single injection of CSL-111, there was a dose- and time-dependent increase of hApoAI, human pre-β HDL, total cholesterol, and triglycerides in serum, consistent with the effects of CSL-111 in humans. However, unlike in humans, there was no measurable increase in cholesteryl esters. Evaluated ex vivo, the ATP binding cassette A1 (ABCA1)- and scavenger receptor type BI (SR-BI)-dependent cholesterol efflux capacity of serum from CSL-111-treated mice was increased compared with serum from vehicle-treated animals. Fractionation by size exclusion chromatography of lipoproteins in serum from treated mice revealed hApoAI in particles the size of endogenous HDL and slightly larger, cholesterol-enriched particles of all sizes, including sizes distinct from endogenous HDL or CSL-111 itself, and triglyceride-enriched particles the size of very-low-density lipoprotein (VLDL). These results suggest that in mouse blood CSL-111 is remodeled and generates enhanced cholesterol efflux capacity which increases mobilization of free cholesterol from peripheral tissues. Our findings complement the previous reports on CSL-111 in human participants and provide data with which to evaluate the potential utility of mouse models in mechanistic studies of HDL-targeting therapies.
authors: Cardiovascular Diseases, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA.
authors: Zhu
authors: Z
authors: Chen
authors: Edward A
authors: EA
authors: O'Neill
authors: Roger D
authors: RD
authors: Meurer
authors: Karen
authors: K
authors: Gagen
authors: Silvi
authors: S
authors: Luell
authors: Sheng-Ping
authors: SP
authors: Wang
authors: Marina
authors: M
authors: Ichetovkin
authors: Betsy
authors: B
authors: Frantz-Wattley
authors: Suzanne
authors: S
authors: Eveland
authors: Alison M
authors: AM
authors: Strack
authors: Timothy S
authors: TS
authors: Fisher
authors: Douglas G
authors: DG
authors: Johns
authors: Carl P
authors: CP
authors: Sparrow
authors: Samuel D
authors: SD
authors: Wright
authors: Brian K
authors: BK
authors: Hubbard
authors: Ester
authors: E
authors: Carballo-Jane
mesh_terms: D000818:Animals; D051837:COUP Transcription Factor II / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D053442:High-Density Lipoproteins, Pre-beta / Q000378:metabolism; D007275:Injections, Intravenous; D008055:Lipids / Q000097:blood*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010713:Phosphatidylcholines
chemical_list: D051837:COUP Transcription Factor II; C519043:CSL-111; D008076:Cholesterol, HDL; D053442:High-Density Lipoproteins, Pre-beta; D008055:Lipids; D010713:Phosphatidylcholines; D002784:Cholesterol