OxLDL up-regulates Niemann-Pick type C1 expression through ERK1/2/COX-2/PPARα-signaling pathway in macrophages.
The Niemann-Pick type C1 (NPC1) is located mainly in the membranes of the late endosome/lysosome and controls the intracellular cholesterol trafficking from the late endosome/lysosome to the plasma membrane. It has been reported that oxidized low-density lipoprotein (oxLDL) can up-regulate NPC1 expression. However, the detailed mechanisms are not fully understood. In this study, we investigated the effect of oxLDL stimulation on NPC1 expression in THP-1 macrophages. Our results showed that oxLDL up-regulated NPC1 expression at both mRNA and protein levels in a dose-dependent and time-dependent manner. In addition, oxLDL also induced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). Treatment with oxLDL significantly increased cyclooxygenase-2 (COX-2) mRNA and protein expression in the macrophages, and these increases were suppressed by the ERK1/2 inhibitor PD98059 or ERK1/2 small interfering RNA (siRNA) treatment. OxLDL up-regulated the expression of peroxisome proliferator-activated receptor α (PPARα) at the mRNA and protein levels, which could be abolished by COX-2 siRNA or COX-2 inhibitor NS398 treatment in these macrophages. OxLDL dramatically elevated cellular cholesterol efflux, which was abrogated by inhibiting ERK1/2 and/or COX-2. In addition, oxLDL-induced NPC1 expression and cellular cholesterol efflux were reversed by PPARα siRNA or GW6471, an antagonist of PPARα. Taken together, these results provide the evidence that oxLDL can up-regulate the expression of the NPC1 through ERK1/2/COX-2/PPARα-signaling pathway in macrophages.
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, China.
Xiaohua
X
Yu
Xiaoxu
X
Li
Guojun
G
Zhao
Ji
J
Xiao
Zhongcheng
Z
Mo
Kai
K
Yin
Zhisheng
Z
Jiang
Yuchang
Y
Fu
Xiaohui
X
Zha
Chaoke
C
Tang
D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D000077296:Niemann-Pick C1 Protein; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D002352:Carrier Proteins; D052246:Cyclooxygenase 2 Inhibitors; C449302:GW 6471; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D010080:Oxazoles; D047493:PPAR alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C099252:oxidized low density lipoprotein; D014443:Tyrosine; D051546:Cyclooxygenase 2