NO-1886 up-regulates Niemann-Pick C1 protein (NPC1) expression through liver X receptor alpha signaling pathway in THP-1 macrophage-derived foam cells.
BACKGROUND
The Niemann-Pick C1 (NPC1) protein regulates the transport of cholesterol from late endosomes/lysosomes to other compartments responsible for maintaining intracellular cholesterol homeostasis. Liver X receptors (LXRs) operate as cholesterol sensors which may protect from cholesterol overload by increasing the amount of free cholesterol in the plasma membrane through inducing NPC1 expression. NO-1886 has been proven to be highly effective at increasing liver X receptor alpha expression and promoting cellular cholesterol efflux. In this study, the effects of NO-1886 on NPC1 expression were investigated in THP-1 macrophage-derived foam cells.


RESULTS
Results showed that NO-1886 markedly increased expression of NPC1 at both mRNA level and protein level in a dose-dependent and time-dependent manner. Cellular cholesterol content was decreased while cholesterol efflux was increased by NO-1886 treatment. In addition, LXR alpha was also up-regulated by NO-1886 treatment. And LXR alpha small interfering RNA completely abolished the promotion effect which was induced by NO-1886.


CONCLUSIONS
These results provide evidence that NO-1886 up-regulates expression of NPC1 through LXR alpha pathway in THP-1 macrophage- derived foam cells.
Ma
Xin
X
Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan, China.
Hu
Yan-Wei
YW
Mo
Zhong-Cheng
ZC
Li
Xiao-Xu
XX
Liu
Xie-Hong
XH
Xiao
Ji
J
Yin
Wei-Dong
WD
Liao
Duan-Fang
DF
Tang
Chao-Ke
CK
D001549:Benzamides / Q000494:pharmacology*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D000071518:Liver X Receptors; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D000077296:Niemann-Pick C1 Protein; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation
D001549:Benzamides; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000960:Hypolipidemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D000071518:Liver X Receptors; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; C000605213:NR1H3 protein, human; D000077296:Niemann-Pick C1 Protein; D009943:Organophosphorus Compounds; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C082137:4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl)benzamide; D002784:Cholesterol