Lipocalin-2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high-fat diet-fed Ob/Ob mice
- Kim, Kyung Eun; Lee, Jaewoong; Shin, Hyun Joo; Jeong, Eun Ae; Jang, Hye Min; Ahn, Yu Jeong; An, Hyeong Seok; Lee, Jong Youl; Shin, Meong Cheol; Kim, Soo Kyoung; Yoo, Won Gi; Kim, Won Ho; Roh, Gu Seob
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- 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.
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- College of Medicine > Department of Medicine > Journal Articles
- 약학대학 > 약학과 > Journal Articles
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