본문 바로가기
KERD
논문KCI 등재

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

성제경|문창종|전태일|이재호|송대규|노구섭|서지혜|Ryu Dongryeol|Kim Mi Kyung|Im Seung-Soon|Jo Yunju|Seo Young-Kyo|Lee Eun-Ho|Kim Do-Young|Lee Young-Seung|Dao Tam|Kim Kyung Eun|Han Eugene|Ryu Seungwan|Shin Minsang|Jung Hye Ra|Osborne Timothy F.
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2024.12|Experimental and Molecular Medicine|제56권 |pp. 1001-1012|DOI 10.1038/s12276-024-01213-2

0

조회

0

다운로드

0

인용

0

참고문헌

주제분류생화학

초록

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.

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.

참고문헌 (49)

  1. Wobser, H., "Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells", Cell Res, 19, pp.996~1005 (2009)
  2. Tomita, K., "Free cholesterol accumulation in hepatic stellate cells : mechan ism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice", Hepa tology, 59, pp.154~169 (2014)
  3. Zhang, C. Y., "Liver fibrosis and hepatic stellate cells : etiology, pathological hallmarks and therapeutic targets", World J. Gastroenterol, 22, pp.10512~10522 (2016)
  4. Pei, K., "An overview of lipid metabolism and nonalcoholic fatty liver disease", Biomed. Res. Int, 2020, pp.4020249~ (2020)
  5. Brankovic, M., "Lipotoxicity as the leading cause of non-alcoholic steatohe patitis", Int. J. Mol. Sci, 23, pp.5146~ (2022)
  6. Li, H., "Crosstalk between liver macrophages and surrounding cells in non alcoholic steatohepatitis", Front. Immunol, 11, pp.1169~ (2020)
  7. Mendez-Sanchez, N., "The cellular pathways of liver fibrosis in non-alcoholic steatohepatitis", Ann. Transl. Med, 8, pp.400~ (2020)
  8. Xu, X., "Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP", Semin. Liver Dis, 33, pp.301~311 (2013)
  9. Ferre, P., "SREBP-1c transcription factor and lipid homeostasis : clinical perspective", Horm. Res, 68, pp.72~82 (2007)
  10. Shao, W., "Expanding roles for SREBP in metabolism", Cell Metab, 16, pp.414~419 (2012)
  11. Nguyen, T. T. P., "SREBP-1c impairs ULK1 sulfhydration-mediated autophagic f lux to promote hepatic steatosis in high-fat-diet-fed mice", Mol. Cell, 81, pp.3820~3832 (2021)
  12. Glaros, T., "Molecular mechanism underlying persistent induction of LCN2 by lipopolysaccharide in kidney fibroblasts", PLoS One, 7, pp.e34633~ (2012)
  13. Moschen, A. R., "Lipocalin-2 : A master mediator of intestinal and metabolic inflammation", Trends Endocrinol. Metab, 28, pp.388~397 (2017)
  14. Jaberi, S. A., "Lipocalin-2 : Structure, function, distribution and role in meta bolic disorders", Biomed. Pharmacother, 142, pp.112002~ (2021)
  15. Cabedo Martinez, A. I., "Biochemical and structural characterization of the interaction between the siderocalin NGAL", LCN2(Neutrophil gelatinase associated lipocalin, J. Biol. Chem, pp.2016, 291[DOI]
  16. Bao, G. H., "The ligands of neutrophil gelatinase-associated Lipocalin", RSC Adv, 5, pp.104363~104374 (2015)
  17. Kang, S. S., "Lipocalin-2 protects the brain during inflammatory conditions", Mol. Psychiatry, 23, pp.344~350 (2018)
  18. Du, H., "Lipocalin-2 alleviates LPS-induced inflammation through alteration of macrophage properties", J. Inflamm. Res, 14, pp.4189~4203 (2021)
  19. Flo, T. H., "Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron", Nature, 432, pp.917~921 (2004)
  20. Holmes, M. A., "Siderocalin(Lcn 2)also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration", Structure, 13, pp.29~41 (2005)
  21. Berger, T., "Lipocalin 2-deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia-reperfusion injury", Proc. Natl Acad. Sci. USA, 103, pp.1834~1839 (2006)
  22. Abella, V., "The potential of lipocalin-2", NGAL as biomarker for inflammatory and metabolic diseases, 2015, pp.20, 565~571
  23. Li, D., "Lipocalin-2 variants and their relationship with cardio-renal risk factors", Front. Endocrinol. (Lausanne), 12, pp.781763~ (2021)
  24. Ryan, J. D., "Hepatic iron is the major determinant of serum ferritin in NAFLD patients", Liver Int, 38, pp.164~173 (2018)
  25. Zhong, F., "Rodent models of nonalcoholic fatty liver disease", Digestion, 101, pp.522~535 (2020)
  26. Shimano, H., "Sterol regulatory element-binding protein-1 as a key tran scription factor for nutritional induction of lipogenic enzyme genes", J. Biol. Chem, 274, pp.35832~35839 (1999)
  27. Seo, Y. K., "Genome-wide analysis of SREBP-1 binding in mouse liver chro matin reveals a preference for promoter proximal binding to a new motif", Proc. Natl Acad. Sci. USA, 106, pp.13765~13769 (2009)
  28. Lee, S., "A dual role of lipocalin 2 in the apoptosis and deramification of activated microglia", J. Immunol, 179, pp.3231~3241 (2007)
  29. Kjeldsen, L., "Identification of neu trophil gelatinase-associated lipocalin as a novel matrix protein of specific granules in human neutrophils", Blood, 83, pp.799~807 (1994)
  30. Asimakopoulou, A., "Lipocalin 2(LCN2)expres sion in hepatic malfunction and therapy", Front. Physiol, 7, pp.430~ (2016)
  31. Yan, Q. W., "The adipokine lipocalin 2 is regulated by obesity and promotes insulin resistance", Diabetes, 56, pp.2533~2540 (2007)
  32. Yang, C., "Liver fibrosis : insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors", Gastroenterology, 124, pp.147~159 (2003)
  33. Dixon, S. J., "Ferroptosis : an iron-dependent form of nonapoptotic cell death", Cell, 149, pp.1060~1072 (2012)
  34. An, H. S., "Lipocalin-2 promotes acute lung inflammation and oxidative stress by enhancing macrophage iron accumulation", Int. J. Biol. Sci, 19, pp.1163~1177 (2023)
  35. Pfister, D., "NASH limits anti-tumour surveillance in immunotherapy-treated HCC", Nature, 592, pp.450~456 (2021)
  36. Gumpper, K., "Lipocalin-2 expression and function in pancreatic diseases", Pancreatology, 20, pp.419~424 (2020)
  37. Xu, G., "Serum lipocalin-2 is a potential biomarker for the clinical diagnosis of nonalcoholic steatohepatitis", Clin. Mol. Hepatol, 27, pp.329~345 (2021)
  38. Ye, D., "Lipocalin-2 mediates non-alcoholic steatohepatitis by promoting neutrophil-macrophage crosstalk via the induction of CXCR2", J. Hepatol, 65, pp.988~997 (2016)
  39. Xiao, X., "Lipocalin 2 : an emerging player in iron homeostasis and inflammation", Annu. Rev. Nutr, 37, pp.103~130 (2017)
  40. Fernandez-Real, J. M., "Effects of iron overload on chronic metabolic diseases", Lancet Diabetes Endocrinol, 2, pp.513~526 (2014)
  41. Cheng, C. F., "Prooxidant mechanisms in iron overload cardiomyo pathy", Biomed. Res. Int, 2013, pp.740573~ (2013)
  42. Dongiovanni, P., "Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target", J. Hepatol, 55, pp.920~932 (2011)
  43. Xia, Y., "Ironing out the details : how iron orchestrates macrophage polar ization", Front. Immunol, 12, pp.669566~ (2021)
  44. Mehta, K. J., "Iron enhances hepatic fibrogenesis and activates transforming growth factor-beta signaling in murine hepatic stellate cells", Am. J. Med. Sci, 355, pp.183~190 (2018)
  45. Zhao, H. W., "TGF-beta", Smad2, Gene, pp.2015, 562[DOI]
  46. Ding, L., "Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-beta-like signaling pathway", J. Clin. Invest, 119, pp.349~361 (2009)
  47. Zhang, J. J., "Zinc mediates the SREBP-SCD axis to regulate lipid metabolism in Caenorhabditis elegans", J. Lipid Res, 58, pp.1845~1854 (2017)
  48. Xiaoli, A. M., "Lipogenic SREBP-1a", c transcription factors acti vate expression of the iron regulator hepcidin, revealing cross-talk between lipid and iron metabolisms, 2019, pp.294, 12743~12753
  49. Xu, Y., "Lipocalin-2 protects against diet-induced nonalcoholic fatty liver disease by targeting hepatocytes", Hepatol. Commun, 3, pp.763~775 (2019)

이 간행물의 다른 논문 (218건)

Big data and deep learning for RNA biologyJeon Hyeonseong, Baek Daehyun, Hwang Hyeonseo, Yeo Nagyeongpp. 1-29RGS19 activates the MYH9/β-catenin/c-Myc positive feedback loop in hepatocellular carcinomaXu Yanan, Ke Shanjia, Lu Shounan, Bai Miaoyu, Yu Hongjun, Yin Bing, Wang Chaoqun, Feng Zhigang, Li Zihao, Huang Jingjing, Li Xinglong, Qian Baolin, Hua Yongliang, Fu Yao, Sun Bei, Wu Yaohua, Ma Yongpp. 1-14Molecular mechanisms of circular RNA translationKim Yoon Ki, Hwang Hyun Jungpp. 1-9The m6A writer RBM15 drives the growth of triple-negative breast cancer cells through the stimulation of serine and glycine metabolismKim Ho, Yun Hye Jin, 이종호, Lee Su Bin, Kim Seok-Ho, Park Yun-Yong, Park Su Hwan, Ju Jin-Sung, Woo Hyunmin, Győrffy Balázs, Kim Eun-jeong, Han Hee Dong, Eyun Seong-ilpp. 1-15Neuron type-specific optogenetic stimulation for differential stroke recovery in chronic capsular infarctKim Ra Gyung, Cho Jongwook, Park Ji-Young, Kim Young Ro, Lee Min-Cheol, Kim Hyoung-Ihlpp. 1-11
원문 보기