Phospholipidosis induced by PPARγ signaling in human bronchial epithelial (BEAS-2B) cells exposed to amiodarone.
Phospholipidosis (PL), a disorder characterized by an accumulation of phospholipids in lysosome-derived multilamellar vesicles owing to abnormal lipid metabolism. Amiodarone (AM), an antiarrhythmic drug, can induce pulmonary PL. First, to evaluate potential mechanisms of phospholipidosis, we found lipid metabolism--related genes by microarray. PPARG, FADS2, and SCD out of these genes were key genes in lipid metabolism and PPAR signaling by AM. The messenger RNA (mRNA) levels of PPARG, FADS2, and SCD were upregulated by AM. The PPARγ antagonist GW9662 was used to investigate the possible involvement of PPARγ as a mediator of AM-induced PL, and FADS2 and SCD small interfering RNAs (siRNAs) were used to examine the involvement of FADS2 and SCD in AM-induced PL. The inhibition of PPARγ by GW9662 significantly attenuated the AM-induced upregulation of SCD and slightly decreased the AM-induced upregulation of FADS2. And the pretreatment of GW9662 significantly decreased the AM-induced uptake of the fluorescent phospholipid analog NBD-PC. The siRNA-mediated gene silencing of FADS2 and SCD also decreased the AM-induced NBD-PC uptake. These results suggest that the activation of the PPARγ signaling pathway, including FADS2 and SCD, may play an important role in AM-induced PL. PPARG, FADS2, and SCD are AM-induced PL-related genes and may serve as potential biomarkers for PL caused by pulmonary toxicity. We also provide evidence for a possible mechanism of PL, the accumulation of phospholipid in the induction of FADS2 and SCD by PPARγ, in AM-induced pulmonary toxicity.
Cellular and Molecular Toxicology Laboratory, Korea Institute of Science and Technology (KIST), Seoul 136-791, Korea.
Mee
M
Song
Youn-Jung
YJ
Kim
Jae-Chun
JC
Ryu
D000638:Amiodarone / Q000009:adverse effects*; D000813:Anilides / Q000494:pharmacology; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018929:Cell Culture Techniques; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D012313:RNA / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000889:Anti-Arrhythmia Agents; D047495:PPAR gamma; D010743:Phospholipids; D034741:RNA, Small Interfering; D012313:RNA; D000638:Amiodarone