Exercise-induced irisin decreases inflammation and improves NAFLD by competitive binding with MD2

Weiwei Zhu, Namood E. Sahar, Hafiz Muhammad Ahmad Javaid, Eun Seon Pak, Guang Liang, Yi Wang, Hunjoo Ha, Joo Young Huh

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Non-alcoholic fatty liver disease (NAFLD) is a global clinical problem. The MD2-TLR4 pathway exacerbates NAFLD progression by promoting inflammation. Long-term exercise is considered to improve NAFLD but the underlying mechanism is still unclear. In this study, we examined the protective effect and molecular mechanism of exercise on high-fat diet (HFD)-induced liver injury. In an HFD-induced NAFLD mouse model, exercise training significantly decreased hepatic steatosis and fibrosis. Interestingly, exercise training blocked the binding of MD2-TLR4 and decreased the downstream inflammatory response. Irisin is a myokine that is highly expressed in response to exercise and exerts anti-inflammatory effects. We found that circulating irisin levels and muscle irisin expression were significantly increased in exercised mice, suggesting that irisin could mediate the effect of exercise on NAFLD. In vitro studies showed that irisin improved lipid metabolism, fibrosis, and inflammation in palmitic acid (PA)-stimulated AML12 cells. Moreover, binding assay results showed that irisin disturbed MD2-TLR4 complex formation by directly binding with MD2 but not TLR4, and interfered with the recognition of stimuli such as PA and lipopolysaccharide with MD2. Our study provides novel evidence that exercise-induced irisin inhibits inflammation via competitive binding with MD2 to improve NAFLD. Thus, irisin could be considered a potential therapy for NAFLD.

Original languageEnglish
Article number3306
Issue number12
StatePublished - Dec 2021

Bibliographical note

Funding Information:
Funding: This study was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education of Korea (No. 2018R1C1B6003470, 2021R1H1A1012282).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • Exercise
  • Inflammasome
  • Irisin
  • MD2
  • Myokine


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