본문 바로가기
KERD
논문KCI 등재

Metabolic improvement and liver regeneration by inhibiting CXXC5 function for non-alcoholic steatohepatitis treatment

최강열|김은환|윤민근|Lee Soung-Hoon|Park Byung-Hyun|서설화
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2022.12|Experimental and Molecular Medicine|제54권 |pp. 1-13|DOI 10.1038/s12276-022-00851-8

2

조회

0

다운로드

1

인용

0

참고문헌

주제분류생화학

초록

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that results from multiple metabolic disorders. Considering the complexity of the pathogenesis, the identification of a factor mediating the multiple pathogenic phenotypes of NASH will be important for treatment. In this study, we found that CXXC5, a negative feedback regulator of the Wnt/β-catenin pathway, was overexpressed with suppression of Wnt/β-catenin signaling and its target genes involved in hepatic metabolism in obese-NASH patients. Cxxc5−/− mice were found to be resistant to NASH pathogenesis with metabolic improvements. KY19334, a small molecule that activates the Wnt/β-catenin pathway via interference of the CXXC5-Dvl interaction, reversed the overall pathogenic features of NASH as Cxxc5−/− mice. The improvement in NASH by KY19334 is attributed to its regenerative effects through restorative activation of the suppressed Wnt/β-catenin signaling. Overall, the pronounced metabolic improvements with the stimulation of liver regeneration by interfering with the CXXC5-Dvl interaction provide a therapeutic approach for NASH.

Abstract

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that results from multiple metabolic disorders. Considering the complexity of the pathogenesis, the identification of a factor mediating the multiple pathogenic phenotypes of NASH will be important for treatment. In this study, we found that CXXC5, a negative feedback regulator of the Wnt/β-catenin pathway, was overexpressed with suppression of Wnt/β-catenin signaling and its target genes involved in hepatic metabolism in obese-NASH patients. Cxxc5−/− mice were found to be resistant to NASH pathogenesis with metabolic improvements. KY19334, a small molecule that activates the Wnt/β-catenin pathway via interference of the CXXC5-Dvl interaction, reversed the overall pathogenic features of NASH as Cxxc5−/− mice. The improvement in NASH by KY19334 is attributed to its regenerative effects through restorative activation of the suppressed Wnt/β-catenin signaling. Overall, the pronounced metabolic improvements with the stimulation of liver regeneration by interfering with the CXXC5-Dvl interaction provide a therapeutic approach for NASH.

참고문헌 (42)

  1. Marchesini, G., "Nonalcoholic fatty liver disease : a feature of the metabolic syndrome", Diabetes, 50, pp.1844~1850 (2001)
  2. Marengo, A., "Liver cancer : connections with obesity, fatty liver, and cirrhosis", Annu. Rev. Med, 67, pp.103~117 (2016)
  3. Sanyal, A. J., "Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities", Gastroenterology, 120, pp.1183~1192 (2001)
  4. Rinella, M. E., "STELLAR 3 and STELLAR 4 : Lessons from the fall of Icarus", J. Hepatol, 73, pp.9~11 (2020)
  5. Sumida, Y., "Current and future pharmacological therapies for NAFLD", NASH, 2018, pp.53, 362~376
  6. Gregor, M. F., "Inflammatory mechanisms in obesity", Annu. Rev. Immunol, 29, pp.415~445 (2011)
  7. Hotamisligil, G. S., "Inflammation and metabolic disorders", Nature, 444, pp.860~867 (2006)
  8. Friedman, S. L., "Mechanisms of NAFLD development and therapeutic strategies", Nat. Med, 24, pp.908~922 (2018)
  9. Ratziu, V., "Current efforts and trends in the treatment of NASH", J. Hepatol, 62, pp.S65~S75 (2015)
  10. Sethi, J. K., "Wnt signalling and the control of cellular metabolism", Biochem. J, 427, pp.1~17 (2010)
  11. Campbell, J. E., "Pharmacology, physiology, and mechanisms of incretin hormone action", Cell Metab, 17, pp.819~837 (2013)
  12. Kalogirou, M., "Treating nonalcoholic steatohepatitis with antidiabetic drugs: Will GLP-1 agonists end the struggle?", World J. Hepatol, 10, pp.790~794 (2018)
  13. Kawakubo, M., "Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects", Sci. Rep, 10, pp.983~ (2020)
  14. Lee, M., "Dipeptidyl peptidase-4 inhibitor protects against non-alcoholic steatohepatitis in mice by targeting TRAIL receptor-mediated lipoapoptosis via modulating hepatic dipeptidyl peptidase-4 expression", Sci. Rep, 10, pp.19429~ (2020)
  15. Hu, M., "Wnt", beta-catenin signaling in murine hepatic transit amplifying progenitor cells, 2007, pp.133, 1579~1591
  16. Bhushan, B., "Inhibition of glycogen synthase kinase 3 accelerated liver regeneration after acetaminophen-induced hepatotoxicity in mice", Am. J. Pathol, 187, pp.543~552 (2017)
  17. Tsukamoto, H., "Morphogens and hepatic stellate cell fate regulation in chronic liver disease", J. Gastroenterol. Hepatol, 27(Suppl 2), pp.94~98 (2012)
  18. Barker, N., "Identification of stem cells in small intestine and colon by marker gene Lgr5", Nature, 449, pp.1003~1007 (2007)
  19. Barker, N., "Lgr5(+ve)stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro", Cell Stem Cell, 6, pp.25~36 (2010)
  20. Jaks, V., "Lgr5 marks cycling, yet long-lived, hair follicle stem cells", Nat. Genet, 40, pp.1291~1299 (2008)
  21. Huch, M., "In vitro expansion of single Lgr5+ liver stem cells induced by Wntdriven regeneration", Nature, 494, pp.247~250 (2013)
  22. Kim, H. Y., "Small molecule inhibitors of the Dishevelled-CXXC5 interaction are new drug candidates for bone anabolic osteoporosis therapy", EMBO Mol. Med, 8, pp.375~387 (2016)
  23. Kim, H. Y., "CXXC5 is a negative-feedback regulator of the Wnt", beta-catenin pathway involved in osteoblast differentiation, 2015, pp.22, 912~920
  24. Choi, S., "CXXC5 mediates growth plate senescence and is a target for enhancement of longitudinal bone growth", Life Sci. Alliance, 2, pp.e201800254~ (2019)
  25. Seo, S. H., "A mixed micellar formulation for the transdermal delivery of an indirubin analog", Pharmaceutics, 12, pp.175~ (2020)
  26. Lu, W. Y., "Hepatic progenitor cells of biliary origin with liver repopulation capacity", Nat. Cell Biol, 17, pp.971~983 (2015)
  27. Despres, J. P., "Abdominal obesity and metabolic syndrome", Nature, 444, pp.881~887 (2006)
  28. Kubota, N., "A high-fat diet and multiple administration of carbon tetrachloride induces liver injury and pathological features associated with nonalcoholic steatohepatitis in mice", Clin. Exp. Pharmacol. Physiol, 40, pp.422~430 (2013)
  29. Ogasawara, M., "A novel and comprehensive mouse model of human nonalcoholic steatohepatitis with the full range of dysmetabolic and histological abnormalities induced by gold thioglucose and a high-fat diet", Liver Int, 31, pp.542~551 (2011)
  30. Hart, K. M., "Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-beta", Sci. Transl. Med, 9, pp.eaal3694~ (2017)
  31. Francque, S., "Pharmacological treatment for non-alcoholic fatty liver disease", Adv. Ther, 36, pp.1052~1074 (2019)
  32. Gomes, A. L., "Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma", Cancer Cell, 30, pp.161~175 (2016)
  33. Oseini, A. M., "Therapies in non-alcoholic steatohepatitis (NASH)", Liver Int, 37(Suppl 1), pp.97~103 (2017)
  34. Baggio, L. L., "Biology of incretins : GLP-1 and GIP", Gastroenterology, 132, pp.2131~2157 (2007)
  35. Dufour, J. F., "Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges", Gut, 69, pp.1877~1884 (2020)
  36. Gastaldelli, A., "Exenatide improves both hepatic and adipose tissue insulin resistance : A dynamic positron emission tomography study", Hepatology, 64, pp.2028~2037 (2016)
  37. Reilly, S. M., "PPAR delta as a therapeutic target in metabolic disease", FEBS Lett, 582, pp.26~31 (2008)
  38. Loomba, R., "The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis : a randomized, phase 2 trial", Hepatology, 67, pp.549~559 (2018)
  39. Mudaliar, S., "Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease", Gastroenterology, 145, pp.574~582.e571 (2013)
  40. Bartelt, A., "Adipose tissue browning and metabolic health", Nat. Rev. Endocrinol, 10, pp.24~36 (2014)
  41. Gustafson, B., "WNT signalling is both an inducer and effector of glucagon-like peptide-1", Diabetologia, 51, pp.1768~1770 (2008)
  42. Ang, C. H., "Lgr5(+)pericentral hepatocytes are self-maintained in normal liver regeneration and susceptible to hepatocarcinogenesis", Proc. Natl Acad. Sci. U. S. A, 116, pp.19530~19540 (2019)

관련 논문AI추천

Inhibiting the cytosolic funaction of CXXC5 accelerates diabetic wound healing by enhancing angiogenesis and skin repair김희진, Choi Kang-Yell, Hwang Yumi, Kim Eunhwan, Lee Jin Woo, Lee Kyoung-Mi, Park Kwang Hwan, Ryu Yeong Chan, Seo Seol Hwa생화학분자생물학회 · Experimental and Molecular Medicine2023 · 제55권 Hepatocyte KCTD17-mediated SERPINA3 inhibition determines liver fibrosis in metabolic dysfunction-associated steatohepatitisCarrer Michele, Jeong Yelin, Jung Kyung Hee, Jung Young Hoon, Kim KyeongJin, Lee Sang Bae, Lee Seongju, Oh Ah-Reum, Pajvani Utpal B., Valenti Luca생화학분자생물학회 · Experimental and Molecular Medicine2025 · 제57권 Wnt signaling in liver regeneration, disease, and cancerGengyi Zou, Jae-Il Park대한간학회 · Clinical and Molecular Hepatology2023 · 제29권 제1호LY6D is crucial for lipid accumulation and inflammation in nonalcoholic fatty liver diseaseDao Tam, Jo Yunju, Kang Yun-Won, Kim Hyeonhui, Kim Yumin, Lee Jibeom, Lee Junguee, Oh Chang-Myung, Park Moon-young, Park Sangkyu, Ryu Dongryeol, Song Ji-Hong생화학분자생물학회 · Experimental and Molecular Medicine2023 · 제55권 Recent research trends and updates on nonalcoholic fatty liver disease김원, 김상균, 이진우, 조용균, Jeong-Ju Yoo, Jong Eun Yeon, Joo Hyun Sohn, KASL-KNSG, Moon Young Kim, Sang Hoon Park대한간학회 · Clinical and Molecular Hepatology2019 · 제25권 제1호Precision medicine in nonalcoholic fatty liver disease: New therapeutic insights from genetics and systems biologyCarlos J. Pirola, Silvia Sookoian대한간학회 · Clinical and Molecular Hepatology2020 · 제26권 제4호

이 간행물의 다른 논문 (191건)

Particulate matter promotes cancer metastasis through increased HBEGF expression in macrophages이효진, Park Jun-Young, Lee Moo-Seung, Kim Dae-Soo, Son Mi-Young, Jeong Jinyoung, 박영준, Cho Young-Lai, Lee Seon-Jin, Park Seung-Ho, Yoon Sung-Jin, Choi Song, Jung Jaeeun, Park Young-Ho, Seo Jinho, Lee Jungwoon, Kim Jang-Seongpp. 1-12WNK3 inhibition elicits antitumor immunity by suppressing PD-L1 expression on tumor cells and activating T-cell function권호근, 김현석, Yoon Hyun Ju, Kim Gi-Cheon, Oh Sejin, Kim Hakhyun, Kim Yong Keon, Lee Yunji, Kim Min Seo, Kwon Gino, Ok Yeon-Supp. 1-14Simultaneous treatment with sorafenib and glucose restriction inhibits hepatocellular carcinoma in vitro and in vivo by impairing SIAH1-mediated mitophagyFeng Ji, Wu Yong, Zhou Jing, Dai Hui-Qi, Zhu Guang-Zhi, Chen Pan-Hong, Wang Li-Ming, Lu Guang, Liao Xi-Wen, Lu Pei-Zhi, Su Wen-Jing, Hooi Shing Chuan, Ye Xin-Pin, Shen Han-Ming, Peng Tao, Lu Guo-Dongpp. 1-15Hypoxia-induced circRNF13 promotes the progression and glycolysis of pancreatic cancerZhao Qiuyan, Zhu Zhonglin, Xiao Wenqin, Zong Guanzhao, Wang Chuanyang, Jiang Weiliang, Li Kai, Shen Jie, Guo Xingya, Cui Jianhua, Guo Lihong, Wan Rongpp. 1-15The transcriptional profile of keloidal Schwann cellsDireder Martin, Wielscher Matthias, Weiss Tamara, Laggner Maria, Copic Dragan, Klas Katharina, Bormann Daniel, Vorstandlechner Vera, Tschachler Erwin, Jan Ankersmit Hendrik, Mildner Michaelpp. 1-15
원문 보기