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

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. Sterol regulatory element-binding protein (SREBP)-1c plays a role in liver fat regulation and is elevated in nonalcoholic steatohepatitis (NASH). Researchers investigated role of SREBP-1c in NASH using mice models and patient samples, focusing on lipocalin-2 (LCN2) regulation. In NASH mice, LCN2 expression was increased, driven by SREBP-1c. LCN2 treatment increased iron accumulation and fibrosis-related gene expression in hepatic stellate cells, dependent on SREBP-1c. LCN2 expression correlated with inflammation and fibrosis in NASH patients. Reduced LCN2 expression protected against NASH in mice lacking SREBP-1c. These findings highlight role of SREBP-1c in NASH via LCN2, revealing a link between iron and lipid metabolism, potentially suggesting new NASH therapy.This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.