25-Hydroxycholesterol regulates cholesterol homeostasis in the murine CATH.a neuronal cell line.
Aberrant oxysterol biosynthesis is implicated in the pathogenesis of neurodegenerative diseases. During the present study we have investigated the effects of exogenously added 25-hydroxycholesterol (25-HC) on transcription of cholesterol biosynthetic genes, sterol-regulatory element binding protein (SREBP) processing and cholesterol biosynthesis in the murine CATH.a neuronal cell line. A single i.p. injection of lipopolysaccharide resulted in robust induction of cholesterol 25-hydroxylase mRNA and protein levels in brains of treated mice. In vitro, 25-HC upregulated the transcription of ATP-binding cassette transporter A1 (ABCA1) and (to a lesser extent) apolipoprotein E (apoE) in CATH.a neurons. Cholesterol biosynthetic gene expression (squalene synthase, HMG-CoA synthase, HMG-CoA reductase, and SREBP2) was downregulated by 25-HC. 25-HC also significantly attenuated proteolytic processing of SREBP2. Finally, 25-HC downregulated cholesterol biosynthesis in CATH.a neurons. Our results demonstrate that 25-HC is a potent effector oxysterol of neuronal cholesterol homeostasis.
Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
Sabine
S
Waltl
Jay V
JV
Patankar
Günter
G
Fauler
Christoph
C
Nusshold
Andreas
A
Ullen
Gerald
G
Eibinger
Andrea
A
Wintersperger
Dagmar
D
Kratky
Ernst
E
Malle
Wolfgang
W
Sattler
D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis* / Q000235:genetics; D006706:Homeostasis; D006888:Hydroxycholesterols / Q000378:metabolism / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D006888:Hydroxycholesterols; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051779:Sterol Regulatory Element Binding Proteins; C007997:25-hydroxycholesterol; D002784:Cholesterol; D013250:Steroid Hydroxylases; C507384:cholesterol 25-hydroxylase