{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T12:39:55Z","timestamp":1789562395527,"version":"build-2803163510"},"reference-count":43,"publisher":"PeerJ","license":[{"start":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T00:00:00Z","timestamp":1687737600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of Zhejiang Province","award":["LY19H200003"],"award-info":[{"award-number":["LY19H200003"]}]},{"name":"National Natural Science Foundation of Zhejiang Province","award":["LY20H200005"],"award-info":[{"award-number":["LY20H200005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>Nonalcoholic steatohepatitis (NASH), a common cause of liver-related morbidity and mortality worldwide, is characterized by inflammation and hepatocellular injury. Our research focuses on lipoprotein-associated phospholipase A2 (Lp-PLA2), an inflammation-related biomarker that has recently garnered interest in the context of NASH due to its potential roles in disease pathogenesis and progression.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>We established a NASH mouse model using a high-fat diet (HFD) and treated it with sh-Lp-PLA2 and\/or rapamycin (an mTOR inhibitor). Lp-PLA2 expression in NASH mice was detected by qRT-PCR. Serum levels of liver function parameters and inflammatory cytokines were detected using corresponding assay kits. We examined pathological changes in liver using hematoxylin-eosin, oil red O, and Masson staining, and observed autophagy through transmission electron microscopy. The protein levels of Lp-PLA2, mTOR, light chain 3 (LC3) II\/I, phosphorylated Janus kinase 2 (p-JAK2)\/JAK2, and phosphorylated signal transducer and activator of transcription 3 (p-STAT3)\/STAT3 were determined by western blotting. Kupffer cells extracted from C57BL\/6J mice were treated to replicate NASH conditions and treated with sh-Lp-PLA2, rapamycin, and\/or a JAK2-inhibitor to further verify the roles and mechanisms of Lp-PLA2 in NASH.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Our data indicate an upregulation of Lp-PLA2 expression in HFD-induced NASH mice. Silencing Lp-PLA2 in NASH mice reduced liver damage and inflammation markers (aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglycerides (TG), tumor necrosis factor-alpha (TNF-\u03b1), and interleukin-6 (IL-6)), while increasing IL-10 levels, an anti-inflammatory cytokine. Additionally, Lp-PLA2 silencing decreased lipid and collagen accumulation and promoted autophagy. The beneficial effects of sh-Lp-PLA2 on NASH were enhanced by rapamycin. Furthermore, Lp-PLA2 silencing resulted in the downregulation of the expression of p-JAK2\/JAK2 and p-STAT3\/STAT3 in NASH mice. Similar results were observed in Kupffer cells treated under NASH conditions; Lp-PLA2 silencing promoted autophagy and repressed inflammation, effects which were potentiated by the addition of rapamycin or a JAK2-inhibitor.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Our findings suggest that silencing Lp-PLA2 promotes autophagy <jats:italic>via<\/jats:italic> deactivating the JAK2\/STAT3 signaling pathway, thereby restraining NASH progression. This highlights the potential therapeutic value of targeting Lp-PLA2, adding a new dimension to our understanding of NASH pathogenesis and treatment strategies.<\/jats:p>\n<\/jats:sec>","DOI":"10.7717\/peerj.15639","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T08:10:38Z","timestamp":1687767038000},"page":"e15639","source":"Crossref","is-referenced-by-count":11,"title":["Lp-PLA2 silencing ameliorates inflammation and autophagy in nonalcoholic steatohepatitis through inhibiting the JAK2\/STAT3 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