Endocrinology and Metabolism

Original Articles

Diabetes, obesity and metabolism
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; Endocrinol Metab. 2024;39(6):908-920. Published online November 5, 2024; DOI: https://doi.org/10.3803/EnM.2024.1984

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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.

Citations

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Targeting the Hepatic Stellate Cell Microenvironment: Nanomedicine Strategies for Liver Fibrosis Therapy
Lulu Pei, Xing Du, Zehao Mao, Kai Ding, Jiangyu Li, Tianqing Liu, Yongmei Zhao
Molecular Pharmaceutics.2026; 23(2): 662. CrossRef
Irisin Attenuates Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension via Ubiquitin‐Mediated Regulation of ENO1
Na Sun, Yong‐Bing Wang, Jing Huang, Run‐Wei Deng, Hui‐Yu He, Lei Gao, Xuan Gao, You‐Li Fan, Yan Cong, Yao‐Lei Guo, Yi‐Qiang Chen, Gui‐Jia Wang, Shao‐Hong Fang, Xia Gu, Bo Yu, Bing‐Xiang Wu
Advanced Science.2025;[Epub] CrossRef
The Influence of Irisin on Selected Organs—The Liver, Kidneys, and Lungs: The Role of Physical Exercise
Maria Ciałowicz, Marek Woźniewski, Eugenia Murawska-Ciałowicz, Piotr Dzięgiel
Cells.2025; 14(16): 1228. CrossRef
Metabolic and immune links between sarcopenia and liver disease
Stanislav Nikolaevich Kotlyarov
World Journal of Hepatology.2025;[Epub] CrossRef
Irisin, the Myokine: Guardian and Mediator in Cardiovascular System
Tian Lan, Xueru Yan, Jie Li, Haoran Gu, Qi Hou, Enpeng He, Qingyuan Yang
Endocrinology, Diabetes & Metabolism.2025;[Epub] CrossRef
Inflammation—Insulin Resistance Crosstalk and the Central Role of Myokines
Maria-Zinaida Dobre, Bogdana Virgolici, Daciana Costina Andrada Dunca-Stefan, Ioana-Cristina Doicin, Iulia-Ioana Stanescu-Spinu
International Journal of Molecular Sciences.2025; 27(1): 60. CrossRef

Diabetes, Obesity and Metabolism
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; Endocrinol Metab. 2022;37(4):620-629. Published online July 22, 2022; DOI: https://doi.org/10.3803/EnM.2022.1412

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Background
Hepatic stellate cells (HSCs) are the central players interacting with multiple cell types in liver fibrosis. The crosstalk between HSCs and macrophages has recently become clearer. Irisin, an exercise-responsive myokine, was known to have a potentially protective role in liver and renal fibrosis, especially in connection with stellate cells. This study investigated the effects of irisin on the interaction between HSCs and macrophages.
Methods
Tamm-Horsfall protein-1 (THP-1) human monocytes were differentiated into macrophages, polarized into the inflammatory M1 phenotype with lipopolysaccharide. Lieming Xu-2 (LX-2) cells, human HSCs, were treated with conditioned media (CM) from M1 macrophages, with or without recombinant irisin. HSCs responses to CM from M1 macrophages were evaluated regarding activation, proliferation, wound healing, trans-well migration, contractility, and related signaling pathway.
Results
CM from M1 macrophages significantly promoted HSC proliferation, wound healing, transwell migration, and contractility, but not activation of HSCs. Irisin co-treatment attenuated these responses of HSCs to CM. However, CM and irisin treatment did not induce any changes in HSC activation. Further, irisin co-treatment alleviated CM-induced increase of phopho-protein kinase B (pAKT), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 (TIMP-1).
Conclusion
These findings suggested that irisin may play a protective role in the pathogenesis of liver fibrosis, especially when working in the crosstalk between HSCs and macrophages.

Citations

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Interactions between hepatic stellate cells and immune cells: Implications for liver fibrosis
Deyu Xie, Yihui Huang, Yitian Yu, Weikai Jin, Xiangting Zhang, Fujun Yu
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Sepsis: Heterogeneity, Immunopathology, and Advances in Therapeutic Strategies
Junxing Qu, Peizhi Li, Zhiheng Sun
The FASEB Journal.2026;[Epub] CrossRef
Irisin and Metastatic Melanoma: Selective Anti-Invasiveness Activity in BRAF Wild-Type Cells
Simona Serratì, Roberta Zerlotin, Michele Manganelli, Roberta Di Fonte, Manuela Dicarlo, Angela Oranger, Graziana Colaianni, Letizia Porcelli, Amalia Azzariti, Stefania Guida, Maria Grano, Silvia Concetta Colucci, Gabriella Guida
International Journal of Molecular Sciences.2025; 26(2): 652. CrossRef
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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
Matrix metalloproteinases induce extracellular matrix degradation through various pathways to alleviate hepatic fibrosis
Liang Shan, Fengling Wang, Dandan Zhai, Xiangyun Meng, Jianjun Liu, Xiongwen Lv
Biomedicine & Pharmacotherapy.2023; 161: 114472. 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
The effect of sarcopenia and serum myokines on prognosis and survival in cirrhotic patients: a multicenter cross-sectional study
Salih Boga, Abdullah Emre Yildirim, Enver Ucbilek, Ali Riza Koksal, Sevil Tokdemir Sisman, Ibrahim Durak, Ilker Sen, Beril Dogu, Erdinc Serin, Ayse Bolat Ucbilek, Makbule Ozge Yildirim, Sukru Mehmet Erturk, Huseyin Alkim, Canan Alkim
European Journal of Gastroenterology & Hepatology.2022; 34(12): 1261. CrossRef

Endocrine Research
Irisin Regulates the Functions of Hepatic Stellate Cells: Hanh Nguyen Dong, So Young Park, Cong Thuc Le, Dae-Hee Choi, Eun-Hee Cho; Endocrinol Metab. 2020;35(3):647-655. Published online September 22, 2020; DOI: https://doi.org/10.3803/EnM.2020.658

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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.

Citations

Citations to this article as recorded by

Interactions between hepatic stellate cells and immune cells: Implications for liver fibrosis
Deyu Xie, Yihui Huang, Yitian Yu, Weikai Jin, Xiangting Zhang, Fujun Yu
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.2026; 1872(1): 168062. CrossRef
Exercise induced irisin mitigates hepatitis in anabolic-androgenic steroids treated rats via modulation of PGC-1-α/PPARγ/Nrf2 and NRF2/NF-κB/TLR4 signaling
Gamal A. Salem, Mohamed Aref, Nanees F. El-Malkey, Haifa A. Alqahtani, Noha ali abd-almotaleb, Mohamed A. Nassan, Hadeel Elsherbiny
Tissue and Cell.2025; 95: 102829. CrossRef
Sarcopenia and metabolic dysfunction-associated steatotic liver disease: The role of exercise-related biomarkers
Marwan S Al-Nimer
World Journal of Hepatology.2025;[Epub] CrossRef
The Influence of Irisin on Selected Organs—The Liver, Kidneys, and Lungs: The Role of Physical Exercise
Maria Ciałowicz, Marek Woźniewski, Eugenia Murawska-Ciałowicz, Piotr Dzięgiel
Cells.2025; 14(16): 1228. CrossRef
Myokine-mediated muscle-organ interactions: Molecular mechanisms and clinical significance
Jia Yi, Junyang Chen, Xinlei Yao, Zihao Zhao, Xinxin Niu, Xia Li, Jiacheng Sun, Yanan Ji, Tongxin Shang, Leilei Gong, Bingqian Chen, Hualin Sun
Biochemical Pharmacology.2025; 242: 117326. CrossRef
Irisin, the Myokine: Guardian and Mediator in Cardiovascular System
Tian Lan, Xueru Yan, Jie Li, Haoran Gu, Qi Hou, Enpeng He, Qingyuan Yang
Endocrinology, Diabetes & Metabolism.2025;[Epub] CrossRef
Amplified response of drug-induced liver fibrosis via immune cell co-culture in a 3D in vitro hepatic fibrosis model
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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
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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
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Clinical Study
Association between Circulating Irisin and C-Reactive Protein Levels: A Systematic Review and Meta-Analysis: Elham Eslampour, Farzad Ebrahimzadeh, Amir Abbasnezhad, Mohammad Zeinali Khosroshahi, Razieh Choghakhori, Omid Asbaghi; Endocrinol Metab. 2019;34(2):140-149. Published online June 24, 2019; DOI: https://doi.org/10.3803/EnM.2019.34.2.140

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Background

Although previous studies have demonstrated that irisin plays an anti-inflammatory role in the body, conflicting results have been reported regarding the correlation between serum levels of irisin and C-reactive protein (CRP). The present meta-analysis was conducted to further investigate the correlation between irisin and CRP levels.

Methods

We systematically searched PubMed, the Cochrane Library, Web of Science, Embase, SCOPUS, and Ovid to retrieve studies assessing the correlation between irisin and CRP levels. Meta-analyses were performed using a random-effects model, and the I² index was used to evaluate heterogeneity.

Results

Of the 428 studies that were initially found, 14 studies with 2,530 participants met the inclusion criteria for the meta-analysis. The pooled effect size was calculated as 0.052 (95% confidence interval, −0.047 to 0.152; P=0.302). Subgroup analyses identified s ignificant, positive, but weak correlations between CRP and irisin levels in cohort studies, studies conducted among healthy participants, studies in which the male-to-female ratio was less than 1, in overweight or obese subjects, and in studies with a sample size of at least 100 participants.

Conclusion

The present meta-analysis found no overall significant correlation between irisin and CRP levels, although a significant positive correlation was found in overweight or obese subjects. Well-designed studies are needed to verify the results of the present meta-analysis.

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Review Article

Obesity and Metabolism
Novel Molecules Regulating Energy Homeostasis: Physiology and Regulation by Macronutrient Intake and Weight Loss: Anna Gavrieli, Christos S. Mantzoros; Endocrinol Metab. 2016;31(3):361-372. Published online July 26, 2016; DOI: https://doi.org/10.3803/EnM.2016.31.3.361

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Excess energy intake, without a compensatory increase of energy expenditure, leads to obesity. Several molecules are involved in energy homeostasis regulation and new ones are being discovered constantly. Appetite regulating hormones such as ghrelin, peptide tyrosine-tyrosine and amylin or incretins such as the gastric inhibitory polypeptide have been studied extensively while other molecules such as fibroblast growth factor 21, chemerin, irisin, secreted frizzle-related protein-4, total bile acids, and heme oxygenase-1 have been linked to energy homeostasis regulation more recently and the specific role of each one of them has not been fully elucidated. This mini review focuses on the above mentioned molecules and discusses them in relation to their regulation by the macronutrient composition of the diet as well as diet-induced weight loss.

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