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Membrane plasmalogen composition and cellular cholesterol regulation: a structure activity study.

Mankidy R, Ahiahonu PW, Ma H, Jayasinghe D, Ritchie SA, Khan MA, Su-Myat KK, Wood PL, Goodenowe DB - Lipids Health Dis (2010)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Phenomenome Discoveries Inc, and Phreedom Pharma, 204-407 Downey Road, Saskatoon, SK S7N 4L8, Canada.

ABSTRACT

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.

Conclusion: 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.

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Scheme showing the syntheses of phosphoethanolamine plasmalogen precursors C1-3, C6-10, and diacylglycerols C4 and C5, test compounds for the study. Reagents: (a) i R1Br, NaH/DMF or R1SO4CH3, NaH/THF, reflux; (ii) 10% HCl, reflux; (b) TBDMS-Cl, imidazole/DMF; (c) R2COCl, DMAP, Pyridine, Toluene; (d) TBAF/THF, Imidazole, - 20°C
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Figure 1: Scheme showing the syntheses of phosphoethanolamine plasmalogen precursors C1-3, C6-10, and diacylglycerols C4 and C5, test compounds for the study. Reagents: (a) i R1Br, NaH/DMF or R1SO4CH3, NaH/THF, reflux; (ii) 10% HCl, reflux; (b) TBDMS-Cl, imidazole/DMF; (c) R2COCl, DMAP, Pyridine, Toluene; (d) TBAF/THF, Imidazole, - 20°C

Mentions: The compounds used for this structure activity relationship study were synthesized from readily available starting materials as shown in the synthetic scheme (Figure 1) and in Table 1.


Membrane plasmalogen composition and cellular cholesterol regulation: a structure activity study.

Mankidy R, Ahiahonu PW, Ma H, Jayasinghe D, Ritchie SA, Khan MA, Su-Myat KK, Wood PL, Goodenowe DB - Lipids Health Dis (2010)

Scheme showing the syntheses of phosphoethanolamine plasmalogen precursors C1-3, C6-10, and diacylglycerols C4 and C5, test compounds for the study. Reagents: (a) i R1Br, NaH/DMF or R1SO4CH3, NaH/THF, reflux; (ii) 10% HCl, reflux; (b) TBDMS-Cl, imidazole/DMF; (c) R2COCl, DMAP, Pyridine, Toluene; (d) TBAF/THF, Imidazole, - 20°C
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2902472&req=5

Figure 1: Scheme showing the syntheses of phosphoethanolamine plasmalogen precursors C1-3, C6-10, and diacylglycerols C4 and C5, test compounds for the study. Reagents: (a) i R1Br, NaH/DMF or R1SO4CH3, NaH/THF, reflux; (ii) 10% HCl, reflux; (b) TBDMS-Cl, imidazole/DMF; (c) R2COCl, DMAP, Pyridine, Toluene; (d) TBAF/THF, Imidazole, - 20°C
Mentions: The compounds used for this structure activity relationship study were synthesized from readily available starting materials as shown in the synthetic scheme (Figure 1) and in Table 1.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Phenomenome Discoveries Inc, and Phreedom Pharma, 204-407 Downey Road, Saskatoon, SK S7N 4L8, Canada.

ABSTRACT

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus