- Diabetes, obesity and metabolism
- Irisin Attenuates Hepatic Stellate Cell Activation and Liver Fibrosis in Bile Duct Ligation Mice Model and Improves Mitochondrial Dysfunction
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Thuy Linh Lai, So Young Park, Giang Nguyen, Phuc Thi Minh Pham, Seon Mee Kang, Jeana Hong, Jae-Ho Lee, Seung-Soon Im, Dae-Hee Choi, Eun-Hee Cho
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Endocrinol Metab. 2024;39(6):908-920. Published online November 5, 2024
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DOI: https://doi.org/10.3803/EnM.2024.1984
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Abstract
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- Background
Liver fibrosis is a common outcome of chronic liver disease and is primarily driven by hepatic stellate cell (HSC) activation. Irisin, a myokine released during physical exercise, is beneficial for metabolic disorders and mitochondrial dysfunction. This study aimed to explore the effects of irisin on liver fibrosis in HSCs, a bile duct ligation (BDL) mouse model, and the associated mitochondrial dysfunction.
Methods In vitro experiments utilized LX-2 cells, a human HSC line, stimulated with transforming growth factor-β1 (TGF-β1), a major regulator of HSC fibrosis, with or without irisin. Mitochondrial function was assessed using mitochondrial fission markers, transmission electron microscopy, mitochondrial membrane potential, and adenosine triphosphate (ATP) production. In vivo, liver fibrosis was induced in mice via BDL, followed by daily intraperitoneal injections of irisin (100 μg/kg/day) for 10 days.
Results In vitro, irisin mitigated HSC activation and reduced reactive oxygen species associated with the TGF-β1/Smad signaling pathway. Irisin restored TGF-β1-induced increases in fission markers (Fis1, p-DRP1) and reversed the decreased expression of TFAM and SIRT3. Additionally, irisin restored mitochondrial membrane potential and ATP production lowered by TGF-β1 treatment. In vivo, irisin ameliorated the elevated liver-to-body weight ratio induced by BDL and alleviated liver fibrosis, as evidenced by Masson’s trichrome staining. Irisin also improved mitochondrial dysfunction induced by BDL surgery.
Conclusion Irisin effectively attenuated HSC activation, ameliorated liver fibrosis in BDL mice, and improved associated mitochondrial dysfunction. These findings highlight the therapeutic potential of irisin for the treatment of liver fibrosis.
- Diabetes, obesity and metabolism
- Phloretin Ameliorates Succinate-Induced Liver Fibrosis by Regulating Hepatic Stellate Cells
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Cong Thuc Le, Giang Nguyen, So Young Park, Hanh Nguyen Dong, Yun Kyung Cho, Jae-Ho Lee, Seung-Soon Im, Dae-Hee Choi, Eun-Hee Cho
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Endocrinol Metab. 2023;38(4):395-405. Published online August 3, 2023
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DOI: https://doi.org/10.3803/EnM.2023.1661
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Abstract
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- Background
Hepatic stellate cells (HSCs) are the major cells which play a pivotal role in liver fibrosis. During injury, extracellular stimulators can induce HSCs transdifferentiated into active form. Phloretin showed its ability to protect the liver from injury, so in this research we would like to investigate the effect of phloretin on succinate-induced HSCs activation in vitro and liver fibrosis in vivo study.
Methods In in vitro, succinate was used to induce HSCs activation, and then the effect of phloretin on activated HSCs was examined. In in vivo, succinate was used to generated liver fibrosis in mouse and phloretin co-treated to check its protection on the liver.
Results Phloretin can reduce the increase of fibrogenic markers and inhibits the proliferation, migration, and contraction caused by succinate in in vitro experiments. Moreover, an upregulation of proteins associated with aerobic glycolysis occurred during the activation of HSCs, which was attenuated by phloretin treatment. In in vivo experiments, intraperitoneal injection of phloretin decreased expression of fibrotic and glycolytic markers in the livers of mice with sodium succinate diet-induced liver fibrosis. These results suggest that aerobic glycolysis plays critical role in activation of HSCs and succinate can induce liver fibrosis in mice, whereas phloretin has therapeutic potential for treating hepatic fibrosis.
Conclusion Intraperitoneal injection of phloretin attenuated succinate-induced hepatic fibrosis and alleviates the succinate-induced HSCs activation.
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Citations
Citations to this article as recorded by 
- The potential of flavonoids in hepatic fibrosis: A comprehensive review
Zhu Wenbo, Han Jianwei, Liu Hua, Tang Lei, Chen Guijuan, Tian Mengfei Phytomedicine.2024; 133: 155932. CrossRef - Advancements in Plant-Based Therapeutics for Hepatic Fibrosis: Molecular Mechanisms and Nanoparticulate Drug Delivery Systems
Alina Ciceu, Ferenc Fenyvesi, Anca Hermenean, Simona Ardelean, Simona Dumitra, Monica Puticiu International Journal of Molecular Sciences.2024; 25(17): 9346. CrossRef
- Diabetes, Obesity and Metabolism
- Gemigliptin Alleviates Succinate-Induced Hepatic Stellate Cell Activation by Ameliorating Mitochondrial Dysfunction
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Giang Nguyen, So Young Park, Dinh Vinh Do, Dae-Hee Choi, Eun-Hee Cho
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Endocrinol Metab. 2022;37(6):918-928. Published online November 15, 2022
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DOI: https://doi.org/10.3803/EnM.2022.1530
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Abstract
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- Background
Dipeptidyl peptidase-4 inhibitors (DPP-4Is) are used clinically as oral antidiabetic agents. Although DPP-4Is are known to ameliorate liver fibrosis, the protective mechanism of DPP-4Is in liver fibrosis remains obscure. In this study, gemigliptin was used to investigate the potential of DPP-4Is to alleviate the progression of liver fibrosis.
Methods To clarify the effects and mechanisms of gemigliptin, we conducted various experiments in LX-2 cells (immortalized human hepatic stellate cells [HSCs], the principal effectors of hepatic fibrogenesis), which were activated by succinate and exhibited elevated expression of α-smooth muscle actin, collagen type 1, and pro-inflammatory cytokines and increased cell proliferation. In vivo, we examined the effects and mechanisms of gemigliptin on a high-fat, high-cholesterol–induced mouse model of nonalcoholic steatohepatitis (NASH).
Results Gemigliptin decreased the expression of fibrogenesis markers and reduced the abnormal proliferation of HSCs. In addition, gemigliptin reduced the succinate-induced production of mitochondrial reactive oxygen species (ROS), intracellular ROS, and mitochondrial fission in HSCs. Furthermore, in the mouse model of NASH-induced liver fibrosis, gemigliptin alleviated both liver fibrosis and mitochondrial dysfunction.
Conclusion Gemigliptin protected against HSC activation and liver fibrosis by alleviating mitochondrial dysfunction and ROS production, indicating its potential as a strategy for preventing the development of liver disease.
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Citations
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- Insulin Resistance, Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Clinical and Experimental Perspective
Inha Jung, Dae-Jeong Koo, Won-Young Lee Diabetes & Metabolism Journal.2024; 48(3): 327. CrossRef - Improvement effect of gemigliptin on salivary gland dysfunction in exogenous methylglyoxal-injected rats
Woo Kwon Jung, Su-Bin Park, Hwa Young Yu, Junghyun Kim Heliyon.2024; 10(8): e29362. CrossRef - Gemigliptin mitigates TGF-β-induced renal fibrosis through FGF21-mediated inhibition of the TGF-β/Smad3 signaling pathway
Jun-Kyu Byun, Gwon-Soo Jung Biochemical and Biophysical Research Communications.2024; : 150425. CrossRef - Interference with mitochondrial function as part of the antifibrogenic effect of Rilpivirine: A step towards novel targets in hepatic stellate cell activation
Ana M. Benedicto, Federico Lucantoni, Isabel Fuster-Martínez, Pedro Diaz-Pozo, Dimitri Dorcaratto, Elena Muñoz-Forner, Victor M. Victor, Juan V. Esplugues, Ana Blas-García, Nadezda Apostolova Biomedicine & Pharmacotherapy.2024; 178: 117206. CrossRef - DPP-IV as a potential candidate in anti-obesity and obesity-related diseases treatment
Xin Guo, Huolun Feng, Liyang Cai, Jiabin Zheng, Yong Li Biomedicine & Pharmacotherapy.2024; 180: 117464. CrossRef - Irisin Attenuates Hepatic Stellate Cell Activation and Liver Fibrosis in Bile Duct Ligation Mice Model and Improves Mitochondrial Dysfunction
Thuy Linh Lai, So Young Park, Giang Nguyen, Phuc Thi Minh Pham, Seon Mee Kang, Jeana Hong, Jae-Ho Lee, Seung-Soon Im, Dae-Hee Choi, Eun-Hee Cho Endocrinology and Metabolism.2024; 39(6): 908. CrossRef - Gemigliptin, a DPP4 inhibitor, ameliorates nonalcoholic steatohepatitis through AMP-activated protein kinase-independent and ULK1-mediated autophagy
Youngmi Song, Hyekyung Yang, Juhee Kim, Yoonjin Lee, Sung-Ho Kim, In-Gu Do, Cheol-Young Park Molecular Metabolism.2023; 78: 101806. CrossRef - DPP-4 Inhibitor in Type 2 Diabetes Mellitus Patient with Non-Alcoholic Fatty Liver Disease: Achieving Two Goals at Once?
Ji Cheol Bae Endocrinology and Metabolism.2022; 37(6): 858. CrossRef
- Endocrine Research
- Irisin Regulates the Functions of Hepatic Stellate Cells
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Hanh Nguyen Dong, So Young Park, Cong Thuc Le, Dae-Hee Choi, Eun-Hee Cho
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Endocrinol Metab. 2020;35(3):647-655. Published online September 22, 2020
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DOI: https://doi.org/10.3803/EnM.2020.658
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7,730
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Abstract
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- Background
Hepatic stellate cells (HSCs) are known to play a fundamental role in the progression of liver fibrosis. Once HSCs are activated, they are involved in proliferation, migration, and contractility which are characteristics of liver fibrogenesis. Recent studies have shown that irisin, a myokine secreted during physical exercise, has a protective effect in various metabolic diseases, especially in renal fibrosis. However, whether irisin is involved in HSC activation and other processes associated with liver fibrosis has not yet been investigated. In this study, we reveal the role of irisin in HSC activation as well as in proliferation, migration, and contractile properties of HSCs in vitro.
Methods LX-2 cells, immortalized human HSCs, were treated with transforming growth factor beta 1 (TGF-β1), a core regulator of HSC fibrosis, with or without irisin, and markers of the aforementioned processes were analyzed. Further, an inflammatory response was stimulated with TGF-β1 and lipopolysaccharide (LPS) in combination with irisin and the expression of cytokines was measured.
Results Recombinant irisin significantly suppressed the expression of TGF-β1-stimulated fibrosis markers including alpha-smooth muscle actin and collagen type 1 alpha 1 and prevented the TGF-β1-induced proliferation, migration, and contractility of LX-2 cells. Additionally, irisin ameliorated the production of interleukin-6 (IL-6) and IL-1β induced by TGF-β1 and LPS treatments.
Conclusion These findings suggested that irisin potently improved the progression of hepatic fibrosis by regulating HSC activation, proliferation, migration, contractility, and HSC-mediated production of inflammatory cytokine.
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Citations
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Hyewon Jung, Mi-lang Kyun, Ji-In Kwon, Jeongha Kim, Ju-Kang Kim, Daeui Park, Yu Bin Lee, Kyoung-Sik Moon Biomaterials Science.2024; 12(24): 6351. CrossRef - Serum Irisin, Myostatin, and Myonectin Correlate with Metabolic Health Markers, Liver Disease Progression, and Blood Pressure in Patients with Metabolic Dysfunction-Associated Fatty Liver Disease and Hypertension
Anna F. Sheptulina, Elvira M. Mamutova, Anastasia Yu. Elkina, Yuriy S. Timofeev, Victoria A. Metelskaya, Anton R. Kiselev, Oxana M. Drapkina Metabolites.2024; 14(11): 584. CrossRef - Irisin Attenuates Hepatic Stellate Cell Activation and Liver Fibrosis in Bile Duct Ligation Mice Model and Improves Mitochondrial Dysfunction
Thuy Linh Lai, So Young Park, Giang Nguyen, Phuc Thi Minh Pham, Seon Mee Kang, Jeana Hong, Jae-Ho Lee, Seung-Soon Im, Dae-Hee Choi, Eun-Hee Cho Endocrinology and Metabolism.2024; 39(6): 908. CrossRef - Potential role of irisin in digestive system diseases
Yueming Zhang, Linxian Zhao, Huan Gao, Jinghui Zhai, Yanqing Song Biomedicine & Pharmacotherapy.2023; 166: 115347. CrossRef - Potential role of irisin in lung diseases and advances in research
Hongna Dong, Xuejiao Lv, Peng Gao, Yuqiu Hao Frontiers in Pharmacology.2023;[Epub] CrossRef - Stem bark of Fraxinus rhynchophylla ameliorates the severity of pancreatic fibrosis by regulating the TGF-β/Smad signaling pathway
Ji-Won Choi, Joon Yeon Shin, Ziqi Zhou, Dong-Uk Kim, Bitna Kweon, Hyuncheol Oh, Youn-Chul Kim, Ho-Joon Song, Gi-Sang Bae, Sung-Joo Park Journal of Investigative Medicine.2022; 70(5): 1285. CrossRef - Circadian rhythms and cancers: the intrinsic links and therapeutic potentials
Li Zhou, Zhe Zhang, Edouard Nice, Canhua Huang, Wei Zhang, Yong Tang Journal of Hematology & Oncology.2022;[Epub] CrossRef - Kinsenoside alleviates inflammation and fibrosis in experimental NASH mice by suppressing the NF-κB/NLRP3 signaling pathway
Yan-fang Deng, Qian-qian Xu, Tian-qi Chen, Jia-xiong Ming, Ya-fen Wang, Li-na Mao, Jia-jun Zhou, Wei-guang Sun, Qun Zhou, Hong Ren, Yong-hui Zhang Phytomedicine.2022; 104: 154241. CrossRef - The potential role of FNDC5/irisin in various liver diseases: awakening the sleeping beauties
Xiaoyu Wang, Lihong Mao, Chaoqun Li, Yangyang Hui, Zihan Yu, Mingyu Sun, Yifan Li, Gaoyue Guo, Wanting Yang, Binxin Cui, Xiaofei Fan, Chao Sun Expert Reviews in Molecular Medicine.2022;[Epub] CrossRef - The Effects of Irisin on the Interaction between Hepatic Stellate Cell and Macrophage in Liver Fibrosis
Dinh Vinh Do, So Young Park, Giang Thi Nguyen, Dae Hee Choi, Eun-Hee Cho Endocrinology and Metabolism.2022; 37(4): 620. CrossRef - Hepatic Steatosis Contributes to the Development of Muscle Atrophy via Inter-Organ Crosstalk
Kenneth Pasmans, Michiel E. Adriaens, Peter Olinga, Ramon Langen, Sander S. Rensen, Frank G. Schaap, Steven W. M. Olde Damink, Florian Caiment, Luc J. C. van Loon, Ellen E. Blaak, Ruth C. R. Meex Frontiers in Endocrinology.2021;[Epub] CrossRef - Physiopathology of Lifestyle Interventions in Non-Alcoholic Fatty Liver Disease (NAFLD)
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