이은호 (계명대학교 의과대학)

한빛사논문

조회241

이은호Eun-Ho Lee

계명대학교 의과대학

Exp. Mol. Med., Apr 16 2024, | https://doi.org/10.1038/s12276-024-01213-2 Loss of SREBP-1c ameliorates iron-induced liver fibrosis by decreasing lipocalin-2

Eun-Ho Lee^1,15, Jae-Ho Lee^1,15, Do-Young Kim¹, Young-Seung Lee², Yunju Jo³, Tam Dao⁴, Kyung Eun Kim⁵, Dae-Kyu Song¹, Ji Hae Seo⁶, Young-Kyo Seo⁷, Je Kyung Seong⁸, Changjong Moon⁹, Eugene Han¹⁰, Mi Kyung Kim¹⁰, Seungwan Ryu¹¹, Minsang Shin¹², Gu Seob Roh⁵, Hye Ra Jung¹³, Timothy F. Osborne¹⁴, Dongryeol Ryu³, Tae-Il Jeon² and Seung-Soon Im¹

¹Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Republic of Korea.

²Department of Animal Science, College of Agriculture and Life Science, Chonnam National University, Gwangju 61186, Republic of Korea.

³Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.

⁴Department of Molecular Cell Biology, Sungkyunkwan University (SKKU) School of Medicine, Suwon 16419, Republic of Korea.

⁵Department of Anatomy, College of Medicine, Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea.

⁶Department of Biochemistry, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea.

⁷Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.

⁸Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea.

⁹Department of Veterinary Anatomy and Animal Behavior, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Republic of Korea.

¹⁰Department of Internal Medicine, Keimyung University School of Medicine, Daegu 42601, Republic of Korea.

¹¹Department of Surgery, Keimyung University School of Medicine, Daegu 42601, Republic of Korea.

¹²Department of Microbiology, School of Medicine, Kyungpook National University, Daegu 42601, Republic of Korea.

¹³Department of Pathology, Keimyung University School of Medicine, Daegu 42601, Republic of Korea.

¹⁴Institute for Fundamental Biomedical Research, Department of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, St. Petersburg, FL 33701, USA.

¹⁵These authors contributed equally: Eun-Ho Lee, Jae-Ho Lee.

Corresponding author : Correspondence to Seung-Soon Im.

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 (CCl ₄), 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 CCl ₄-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.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-17)
연구진국내(교신)+국외 연구진
분야 생명과학 > 생리학

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