Membrane plasmalogen composition and cellular cholesterol regulation: a structure activity study.
BACKGROUND
Disrupted cholesterol regulation leading to increased circulating and membrane cholesterol levels is implicated in many age-related chronic diseases such as cardiovascular disease (CVD), Alzheimer's disease (AD), and cancer. In vitro and ex vivo cellular plasmalogen deficiency models have been shown to exhibit impaired intra- and extra-cellular processing of cholesterol. Furthermore, depleted brain plasmalogens have been implicated in AD and serum plasmalogen deficiencies have been linked to AD, CVD, and cancer.


RESULTS
Using plasmalogen deficient (NRel-4) and plasmalogen sufficient (HEK293) cells we investigated the effect of species-dependent plasmalogen restoration/augmentation on membrane cholesterol processing. The results of these studies indicate that the esterification of cholesterol is dependent upon the amount of polyunsaturated fatty acid (PUFA)-containing ethanolamine plasmalogen (PlsEtn) present in the membrane. We further elucidate that the concentration-dependent increase in esterified cholesterol observed with PUFA-PlsEtn was due to a concentration-dependent increase in sterol-O-acyltransferase-1 (SOAT1) levels, an observation not reproduced by 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibition.


CONCLUSIONS
The present study describes a novel mechanism of cholesterol regulation that is consistent with clinical and epidemiological studies of cholesterol, aging and disease. Specifically, the present study describes how selective membrane PUFA-PlsEtn enhancement can be achieved using 1-alkyl-2-PUFA glycerols and through this action reduce levels of total and free cholesterol in cells.
Mankidy
Rishikesh
R
Phenomenome Discoveries Inc, and Phreedom Pharma, 204-407 Downey Road, Saskatoon, SK S7N 4L8, Canada.
Ahiahonu
Pearson Wk
PW
Ma
Hong
H
Jayasinghe
Dushmanthi
D
Ritchie
Shawn A
SA
Khan
Mohamed A
MA
Su-Myat
Khine K
KK
Wood
Paul L
PL
Goodenowe
Dayan B
DB
D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004951:Esterification; D005231:Fatty Acids, Unsaturated / Q000737:chemistry; D005990:Glycerol; D006801:Humans; D010955:Plasmalogens / Q000032:analysis / Q000737:chemistry*; D013045:Species Specificity; D002785:Sterol O-Acyltransferase / Q000032:analysis; D013329:Structure-Activity Relationship
D005231:Fatty Acids, Unsaturated; D010955:Plasmalogens; C020791:phosphatidal ethanolamines; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1; D005990:Glycerol