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Lipocalin-2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high-fat diet-fed Ob/Ob mice

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dc.contributor.authorKim, Kyung Eun-
dc.contributor.authorLee, Jaewoong-
dc.contributor.authorShin, Hyun Joo-
dc.contributor.authorJeong, Eun Ae-
dc.contributor.authorJang, Hye Min-
dc.contributor.authorAhn, Yu Jeong-
dc.contributor.authorAn, Hyeong Seok-
dc.contributor.authorLee, Jong Youl-
dc.contributor.authorShin, Meong Cheol-
dc.contributor.authorKim, Soo Kyoung-
dc.contributor.authorYoo, Won Gi-
dc.contributor.authorKim, Won Ho-
dc.contributor.authorRoh, Gu Seob-
dc.date.accessioned2024-05-02T05:36:46Z-
dc.date.available2024-05-02T05:36:46Z-
dc.date.created2024-04-29-
dc.date.created2024-04-29-
dc.date.issued2023-03-
dc.identifier.citationHepatology, Vol.77 No.3, pp.888-901-
dc.identifier.issn0270-9139-
dc.identifier.urihttps://hdl.handle.net/10371/200390-
dc.description.abstractBackground and Aims In obesity and type 2 diabetes mellitus, leptin promotes insulin resistance and contributes to the progression of NASH via activation of hepatic stellate cells (HSCs). However, the pathogenic mechanisms that trigger HSC activation in leptin-deficient obesity are still unknown. This study aimed to determine how HSC-targeting lipocalin-2 (LCN2) mediates the transition from simple steatosis to NASH. Approach and Results Male wild-type (WT) and ob/ob mice were fed a high-fat diet (HFD) for 20 weeks to establish an animal model of NASH with fibrosis. Ob/ob mice were subject to caloric restriction or recombinant leptin treatment. Double knockout (DKO) mice lacking both leptin and lcn2 were also fed an HFD for 20 weeks. In addition, HFD-fed ob/ob mice were treated with gadolinium trichloride to deplete Kupffer cells. The LX-2 human HSCs and primary HSCs from ob/ob mice were used to investigate the effects of LCN2 on HSC activation. Serum and hepatic LCN2 expression levels were prominently increased in HFD-fed ob/ob mice compared with normal diet-fed ob/ob mice or HFD-fed WT mice, and these changes were closely linked to liver fibrosis and increased hepatic alpha-SMA/matrix metalloproteinase 9 (MMP9)/signal transducer and activator of transcription 3 (STAT3) protein levels. HFD-fed DKO mice showed a marked reduction of alpha-SMA protein compared with HFD-fed ob/ob mice. In particular, the colocalization of LCN2 and alpha-SMA was increased in HSCs from HFD-fed ob/ob mice. In primary HSCs from ob/ob mice, exogenous LCN2 treatment induced HSC activation and MMP9 secretion. By contrast, LCN2 receptor 24p3R deficiency or a STAT3 inhibitor reduced the activation and migration of primary HSCs. Conclusions LCN2 acts as a key mediator of HSC activation in leptin-deficient obesity via alpha-SMA/MMP9/STAT3 signaling, thereby exacerbating NASH.-
dc.language영어-
dc.publisherJohn Wiley & Sons Inc.-
dc.titleLipocalin-2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high-fat diet-fed Ob/Ob mice-
dc.typeArticle-
dc.identifier.doi10.1002/hep.32569-
dc.citation.journaltitleHepatology-
dc.identifier.wosid000826113500001-
dc.identifier.scopusid2-s2.0-85134160437-
dc.citation.endpage901-
dc.citation.number3-
dc.citation.startpage888-
dc.citation.volume77-
dc.description.isOpenAccessY-
dc.contributor.affiliatedAuthorYoo, Won Gi-
dc.type.docTypeArticle-
dc.description.journalClass1-
dc.subject.keywordPlusMATRIX METALLOPROTEINASES-
dc.subject.keywordPlusLIVER-DISEASE-
dc.subject.keywordPlusUP-REGULATION-
dc.subject.keywordPlusDIFFERENTIATION-
dc.subject.keywordPlusMECHANISMS-
dc.subject.keywordPlusFIBROSIS-
dc.subject.keywordPlusINFECTION-
dc.subject.keywordPlusMODELS-
dc.subject.keywordPlusMMP-9-
dc.subject.keywordPlusADRP-
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  • College of Veterinary Medicine
  • Department of Veterinary Medicine
Research Area Microbiology, Parasitology, Tropical Medicine

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