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Loss of SREBP-1c ameliorates iron-induced liver fibrosis by decreasing lipocalin-2

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Author(s)
Eun-Ho LeeJae-Ho LeeDo-Young KimYoung-Seung LeeYunju JoTam DaoKyung Eun KimDae-Kyu SongJi Hae SeoYoung-Kyo SeoJe Kyung SeongChangjong MoonEugene HanMi Kyung KimSeungwan RyuMinsang ShinGu Seob RohHye Ra JungTimothy F. OsborneDongryeol RyuTae-Il JeonSeung-Soon Im
Keimyung Author(s)
Song, Dae KyuSeo, Ji HyeHan, Eu GeneKim, Mi KyungRyu, Seung WanJung, Hye Ra
Department
Dept. of Physiology (생리학)
Dept. of Biochemistry (생화학)
Dept. of Internal Medicine (내과학)
Dept. of Surgery (외과학)
Dept. of Pathology (병리학)
Journal Title
Exp Mol Med
Issued Date
2024
Volume
56
Abstract
Sterol regulatory element-binding protein (SREBP)-1c is involved in cellular lipid homeostasis and cholesterol biosynthesis and is highly increased in nonalcoholic steatohepatitis (NASH). However, the molecular mechanism by which SREBP-1c regulates hepatic stellate cells (HSCs) activation in NASH animal models and patients have not been fully elucidated. In this study, we examined the role of SREBP-1c in NASH and the regulation of LCN2 gene expression. Wild-type and SREBP-1c knockout (1cKO) mice were fed a high-fat/high-sucrose diet, treated with carbon tetrachloride (CCl4), and subjected to lipocalin-2 (LCN2) overexpression. The role of LCN2 in NASH progression was assessed using mouse primary hepatocytes, Kupffer cells, and HSCs. LCN2 expression was examined in samples from normal patients and those with NASH. LCN2 gene expression and secretion increased in CCl4-induced liver fibrosis mice model, and SREBP-1c regulated LCN2 gene transcription. Moreover, treatment with holo-LCN2 stimulated intracellular iron accumulation and fibrosis-related gene expression in mouse primary HSCs, but these effects were not observed in 1cKO HSCs, indicating that SREBP-1c-induced LCN2 expression and secretion could stimulate HSCs activation through iron accumulation. Furthermore, LCN2 expression was strongly correlated with inflammation and fibrosis in patients with NASH. Our findings indicate that SREBP-1c regulates Lcn2 gene expression, contributing to diet-induced NASH. Reduced Lcn2 expression in 1cKO mice protects against NASH development. Therefore, the activation of Lcn2 by SREBP-1c establishes a new connection between iron and lipid metabolism, affecting inflammation and HSCs activation. These findings may lead to new therapeutic strategies for NASH.
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