2. Academic Validation
  3. Didymin alleviates metabolic dysfunction-associated fatty liver disease (MAFLD) via the stimulation of Sirt1-mediated lipophagy and mitochondrial biogenesis

Didymin alleviates metabolic dysfunction-associated fatty liver disease (MAFLD) via the stimulation of Sirt1-mediated lipophagy and mitochondrial biogenesis

  • J Transl Med. 2023 Dec 19;21(1):921. doi: 10.1186/s12967-023-04790-4.
Jing-Wen Yang 1,  Ying Zou 1,  Jun Chen 1,  Chen Cui 2,  Jia Song 1,  Meng-Meng Yang 1,  Jing Gao 1,  Hui-Qing Hu 1,  Long-Qing Xia 1,  Li-Ming Wang 1,  Xiao-Yu Lv 1,  Li Chen 1 3 4 5 6 7,  Xin-Guo Hou 8 9 10 11 12 13
Affiliations

Affiliations

  • 1 Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
  • 2 Department of Endocrinology, The Second Hospital of Shandong University, Jinan, China.
  • 3 Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.
  • 4 Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, China.
  • 5 Institute of Endocrine and Metabolic Diseases, Shandong University, Jinan, China.
  • 6 National Key Laboratory for Innovation and Transformation of Luobing Theory, Jinan, China.
  • 7 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Jinan, China.
  • 8 Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China. houxinguo@sdu.edu.cn.
  • 9 Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China. houxinguo@sdu.edu.cn.
  • 10 Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, China. houxinguo@sdu.edu.cn.
  • 11 Institute of Endocrine and Metabolic Diseases, Shandong University, Jinan, China. houxinguo@sdu.edu.cn.
  • 12 National Key Laboratory for Innovation and Transformation of Luobing Theory, Jinan, China. houxinguo@sdu.edu.cn.
  • 13 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Jinan, China. houxinguo@sdu.edu.cn.
PMID: 38115075 DOI: 10.1186/s12967-023-04790-4
Abstract

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is one of the most prevalent metabolic syndromes worldwide. However, no approved pharmacological treatments are available for MAFLD. Chenpi, one kind of dried peel of citrus fruits, has traditionally been utilized as a medicinal herb for liver diseases. Didymin is a newly identified oral bioactive dietary flavonoid glycoside derived from Chenpi. In this study, we investigated the therapeutic potential of Didymin as an anti-MAFLD drug and elucidated its underlying mechanisms.

Methods: High-fat diet (HFD)-induced MAFLD mice and alpha mouse liver 12 (AML12) cells were utilized to evaluate the effects and mechanisms of Didymin in the treatment of MAFLD. Liver weight, serum biochemical parameters, and liver morphology were examined to demonstrate the therapeutic efficacy of Didymin in MAFLD treatment. RNA-seq analysis was performed to identify potential pathways that could be affected by Didymin. The impact of Didymin on SIRT1 was corroborated through western blot, molecular docking analysis, microscale thermophoresis (MST), and deacetylase activity assay. Then, a SIRT1 Inhibitor (EX-527) was utilized to confirm that Didymin alleviates MAFLD via SIRT1. Western blot and additional assays were used to investigate the underlying mechanisms.

Results: Our results suggested that Didymin may possess therapeutic potential against MAFLD in vitro and in vivo. By promoting SIRT1 expression as well as directly binding to and activating SIRT1, Didymin triggers downstream pathways that enhance mitochondrial biogenesis and function while reducing Apoptosis and enhancing lipophagy.

Conclusions: These suggest that Didymin could be a promising medication for MAFLD treatment. Furthermore, its therapeutic effects are mediated by SIRT1.

Keywords

Apoptosis; Didymin; FoxO3a; Lipophagy; MAFLD; Mitochondrial function; PGC-1α; Sirt1.

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