Cyclosporin A inhibits apolipoprotein A-I-induced early events in cellular cholesterol homeostasis in rat astrocytes.
In the biogenesis of HDL by exogenous apolipoprotein (apo) A-I in rat astrocytes, apoA-I induced translocation of phospholipase Cgamma (PLCgamma) and PKCalpha to cytosolic lipid protein particle (CLPP) [Ito et al., 2004. J. Lipid Res. 45, 2269] and caused tyrosine-phosphorylation of PLCgamma in CLPP in the initial 5 min. It also induced translocation of caveolin-1 and newly synthesized cholesterol and phospholipid to CLPP, and increased cholesterol biosynthesis prior to the HDL biogenesis [Ito et al., 2002a. J. Biol. Chem. 277, 7929]. Cyclosporin A (CsA), an indirect inhibitor of protein phosphatase 2B (PP2B) and a potential inhibitor of ABC transporter A1 (ABCA1), suppressed all of these apoA-I-induced cellular events. CsA, however, did not affect the basal lipid release by the production of HDL with endogenous apoE, except for moderate decrease of its cholesterol content. Direct inhibitors of PP2B, inhibited only the release of lipids by apoA-I and had no effect on other apoA-I-induced events. CsA thus interferes with cellular cholesterol homeostasis independently of PP2B inhibition, perhaps by direct inhibition of ABCA1 reactivity to exogenous apoA-I, although PP2B may be involved in the lipid release step. CsA could therefore cause some neurological side effects by interfering with cellular cholesterol homeostasis in the brain.
Kheirollah
Alireza
A
Biochemistry, Cell Biology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
Ito
Jin-ichi
J
Nagayasu
Yuko
Y
Lu
Rui
R
Yokoyama
Shinji
S
D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects*; D015153:Blotting, Western / Q000379:methods; D002458:Cell Fractionation / Q000379:methods; D002784:Cholesterol / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation; D050356:Lipid Metabolism / Q000187:drug effects; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D016632:Apolipoprotein A-I; D004791:Enzyme Inhibitors; D014443:Tyrosine; D016572:Cyclosporine; D002784:Cholesterol; D051966:Phospholipase C gamma