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Despite its efficacy, olanzapine's prolonged use has been associated with an increased risk of cardiovascular diseases and nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanism remains unclear. Proprotein convertase subtilisin kexin type 9 (PCSK9) plays a crucial role in lipid metabolism and is involved in NAFLD pathogenesis via an unknown mechanism. This study aims to investigate the role of PCSK9 in olanzapine\u2010induced NAFLD. C57BL\/6J mice and HepG2 and AML12 cell lines were treated with varying concentrations of olanzapine to examine the effects of olanzapine on PCSK9 and lipid metabolism. PCSK9 levels were manipulated using recombinant proteins, plasmids, and small interfering RNAs in\u00a0vitro, and the effects on hepatic lipid accumulation and gene expression related to lipid metabolism were assessed. Olanzapine treatment significantly increased PCSK9 levels in both animal and cell line models, correlating with elevated lipid accumulation. PCSK9 manipulation demonstrated its central role in mediating hepatic steatosis through both receptor\u2010dependent pathways (impacting NPC1L1) and receptor\u2010independent pathways (affecting lipid synthesis, uptake, and cholesterol biosynthesis). Interestingly, upregulation of SREBP\u20101c, rather than SREBP\u20102, was identified as a key driver of PCSK9 increase in olanzapine\u2010induced NAFLD. Our findings establish PCSK9 as a pivotal factor in olanzapine\u2010induced NAFLD, influencing both receptor\u2010related and metabolic pathways. This highlights PCSK9 inhibitors as potential therapeutic agents for managing NAFLD in schizophrenia patients treated with olanzapine.<\/jats:p>","DOI":"10.1096\/fj.202301748r","type":"journal-article","created":{"date-parts":[[2024,2,15]],"date-time":"2024-02-15T10:19:26Z","timestamp":1707992366000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["<scp>PCSK9<\/scp>\n                    dysregulates cholesterol homeostasis and triglyceride metabolism in olanzapine\u2010induced hepatic steatosis via both receptor\u2010dependent and receptor\u2010independent pathways"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9946-2793","authenticated-orcid":false,"given":"Piaopiao","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, The Second Xiangya Hospital Central South University  Changsha Hunan 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