Role of activated endocannabinoid system in regulation of cellular cholesterol metabolism in macrophages.
OBJECTIVE
Evidence from recent studies suggests that the endocannabinoid system participates in the regulation of lipid metabolism and body composition. We hypothesize that the system is activated by oxidized low-density lipoprotein (oxLDL) and regulates cellular cholesterol metabolism in macrophages.


RESULTS
Primary peritoneal macrophages isolated from Sprague-Dawley rats and RAW264.7 mice macrophages were cultured. A liquid chromatography/mass spectrometry (LC/MS) system was used to measure the endocannabinoid anandamide (AEA), 2-arachidonoylglycerol (2-AG), and cellular cholesterol levels in macrophages. The regulatory mechanisms of cellular cholesterol metabolism were also investigated by molecular biology methods. The results showed that the endocannabinoid system in macrophages was activated by oxLDL through elevation of the AEA and 2-AG levels and the up-regulation of the cannabinoid CB1 and CB2 receptor expression. Win55,212-2, a synthetic cannabinoid, promotes cellular cholesterol accumulation in macrophages, which was associated with an increase in the expression of CD36 and a decrease in the expression of ATP-binding cassette protein A1 (ABCA1) as mediated by an up-regulated peroxisome proliferator-activated receptor gamma (PPARgamma). AM251, a selective cannabinoid CB1 receptor antagonist, impaired the abilities of Win55,212-2-treated macrophages to accumulate cholesterol by down-regulating CD36 receptor expression and up-regulating ABCA1 expression.


CONCLUSIONS
We have demonstrated, for the first time, that the endocannabinoid system in macrophages is activated by oxLDL and that the activated endocannabinoid system promotes cellular cholesterol accumulation in macrophages. The results also indicate that selectively blocking the CB1 receptor can reduce oxLDL accumulation in macrophages, which might represent a promising therapeutic strategy for atherosclerosis.
Jiang
Li-sheng
LS
Department of Geriatrics, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
Pu
Jun
J
Han
Zhi-hua
ZH
Hu
Liu-hua
LH
He
Ben
B
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D048588:Benzoxazines / Q000494:pharmacology; D018955:CD36 Antigens / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001095:Arachidonic Acids; D048588:Benzoxazines; D018955:CD36 Antigens; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D008077:Lipoproteins, LDL; D009025:Morpholines; D009281:Naphthalenes; D047495:PPAR gamma; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C099252:oxidized low density lipoprotein; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C094503:glyceryl 2-arachidonate; D002784:Cholesterol; C078814:anandamide