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Lipocalin-2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high-fat diet-fed Ob/Ob mice
DC Field | Value | Language |
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dc.contributor.author | Kim, Kyung Eun | - |
dc.contributor.author | Lee, Jaewoong | - |
dc.contributor.author | Shin, Hyun Joo | - |
dc.contributor.author | Jeong, Eun Ae | - |
dc.contributor.author | Jang, Hye Min | - |
dc.contributor.author | Ahn, Yu Jeong | - |
dc.contributor.author | An, Hyeong Seok | - |
dc.contributor.author | Lee, Jong Youl | - |
dc.contributor.author | Shin, Meong Cheol | - |
dc.contributor.author | Kim, Soo Kyoung | - |
dc.contributor.author | Yoo, Won Gi | - |
dc.contributor.author | Kim, Won Ho | - |
dc.contributor.author | Roh, Gu Seob | - |
dc.date.accessioned | 2024-05-02T05:36:46Z | - |
dc.date.available | 2024-05-02T05:36:46Z | - |
dc.date.created | 2024-04-29 | - |
dc.date.created | 2024-04-29 | - |
dc.date.issued | 2023-03 | - |
dc.identifier.citation | Hepatology, Vol.77 No.3, pp.888-901 | - |
dc.identifier.issn | 0270-9139 | - |
dc.identifier.uri | https://hdl.handle.net/10371/200390 | - |
dc.description.abstract | Background 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.language | 영어 | - |
dc.publisher | John Wiley & Sons Inc. | - |
dc.title | Lipocalin-2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high-fat diet-fed Ob/Ob mice | - |
dc.type | Article | - |
dc.identifier.doi | 10.1002/hep.32569 | - |
dc.citation.journaltitle | Hepatology | - |
dc.identifier.wosid | 000826113500001 | - |
dc.identifier.scopusid | 2-s2.0-85134160437 | - |
dc.citation.endpage | 901 | - |
dc.citation.number | 3 | - |
dc.citation.startpage | 888 | - |
dc.citation.volume | 77 | - |
dc.description.isOpenAccess | Y | - |
dc.contributor.affiliatedAuthor | Yoo, Won Gi | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.subject.keywordPlus | MATRIX METALLOPROTEINASES | - |
dc.subject.keywordPlus | LIVER-DISEASE | - |
dc.subject.keywordPlus | UP-REGULATION | - |
dc.subject.keywordPlus | DIFFERENTIATION | - |
dc.subject.keywordPlus | MECHANISMS | - |
dc.subject.keywordPlus | FIBROSIS | - |
dc.subject.keywordPlus | INFECTION | - |
dc.subject.keywordPlus | MODELS | - |
dc.subject.keywordPlus | MMP-9 | - |
dc.subject.keywordPlus | ADRP | - |
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