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

Eun Ho Lee, Jae Ho Lee, Do Young Kim, Young Seung Lee, Yunju Jo, Tam Dao, Kyung Eun Kim, Dae Kyu Song, Ji Hae Seo, Young Kyo Seo, Je Kyung Seong, Changjong Moon, Eugene Han, Mi Kyung Kim, Seungwan Ryu, Minsang Shin, Gu Seob Roh, Hye Ra Jung, Timothy F. Osborne, Dongryeol RyuTae Il Jeon, Seung Soon Im

Research output: Contribution to journalArticlepeer-review

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. (Figure presented.)

Original languageEnglish
Pages (from-to)1001-1012
Number of pages12
JournalExperimental and Molecular Medicine
Volume56
Issue number4
DOIs
StatePublished - Apr 2024

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