Song, Mee Kim, Youn-Jung Ryu, Jae-Chun 2024-01-20T17:32:44Z 2024-01-20T17:32:44Z 2021-09-02 2011-03 1096-6080 https://pubs.kist.re.kr/handle/201004/130609 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 PPAR gamma antagonist GW9662 was used to investigate the possible involvement of PPAR gamma 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 PPAR gamma 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 PPAR gamma 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 PPAR gamma, in AM-induced pulmonary toxicity. English OXFORD UNIV PRESS DRUG-INDUCED PHOSPHOLIPIDOSIS ACTIVATED RECEPTOR-GAMMA GENE-EXPRESSION LUNG INCREASES TOXICITY FIBROSIS KINETICS ALPHA LIVER Phospholipidosis Induced by PPAR gamma Signaling in Human Bronchial Epithelial (BEAS-2B) Cells Exposed to Amiodarone Article 10.1093/toxsci/kfq361 1 TOXICOLOGICAL SCIENCES, v.120, no.1, pp.98 - 108 TOXICOLOGICAL SCIENCES 120 1 98 108 scie scopus 000287747800009 2-s2.0-79952080730 Toxicology Toxicology Article DRUG-INDUCED PHOSPHOLIPIDOSIS ACTIVATED RECEPTOR-GAMMA GENE-EXPRESSION LUNG INCREASES TOXICITY FIBROSIS KINETICS ALPHA LIVER phospholipidosis FADS2 SCD amiodarone