Hesperitin prevents non-alcoholic steatohepatitis by modulating mitochondrial dynamics and mitophagy via the AMPKα-Drp1/PINK1-Parkin signaling pathway

Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Jan;1870(1):159570. doi: 10.1016/j.bbalip.2024.159570. Epub 2024 Oct 23.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is becoming a global public health burden, yet effective therapeutic strategies are notably lacking. NAFLD development may be mediated by mitochondrial dysfunction, according to new research. Producing mitochondrial regulators from plant-based substances to treat mitochondrial dysfunction is an appealing approach to treating NAFLD. Hesperetin (HES) is a flavonoid that is found naturally and is a member of the flavanone family. This study aims to clarify the mechanism of HES in preventing NAFLD which is caused by a high-fat diet (HFD). Serum and liver biochemical parameters, liver histology, lipid profiles, and mitochondrial function were evaluated in HFD-induced NAFLD Sprague-Dawley (SD) rats. HES treatment significantly reduced body weight gain, liver weight, and the liver index, while also improving hepatic steatosis, lipid metabolism disorders, and mitochondrial dysfunction in rats with NAFLD. The mechanism was investigated and confirmed using western blot and real-time quantitative polymerase chain reaction (RT-qPCR). We showed that in the liver of NAFLD rats, HES decreased the expression of dynamic-related protein 1 (Drp1), phosphorylated Drp1 at serine-616 (Drp1-pS616) and induced phosphorylated Drp1 at serine-637 (Drp1-pS637), PTEN-induced kinase 1 (PINK1), and E3 Ubiquitin-Protein Ligase Parkin (Parkin) via an AMP-activated protein kinase alpha (AMPKα)-dependent mechanism. Moreover, HES increased the expression of the mitochondrial fusion proteins mitofusin-2 (Mfn2) and optic atrophy 1 (Opa1) while suppressing the expression of fission protein 1 (Fis1). In this work, we identify a unique mechanism by which HES prevents NAFLD from developing. HES may be an attractive potential therapeutic agent to cure NAFLD.

Keywords: AMP-activated protein kinase alpha (AMPKα); Hesperitin (HES); Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; Non-alcoholic fatty liver disease (NAFLD).

MeSH terms

  • AMP-Activated Protein Kinases* / genetics
  • AMP-Activated Protein Kinases* / metabolism
  • Animals
  • Diet, High-Fat / adverse effects
  • Dynamins* / genetics
  • Dynamins* / metabolism
  • Hesperidin* / pharmacology
  • Hesperidin* / therapeutic use
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mitochondrial Dynamics* / drug effects
  • Mitophagy* / drug effects
  • Non-alcoholic Fatty Liver Disease* / drug therapy
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Non-alcoholic Fatty Liver Disease* / pathology
  • Non-alcoholic Fatty Liver Disease* / prevention & control
  • Protein Kinases* / genetics
  • Protein Kinases* / metabolism
  • Rats
  • Rats, Sprague-Dawley*
  • Signal Transduction* / drug effects
  • Ubiquitin-Protein Ligases* / genetics
  • Ubiquitin-Protein Ligases* / metabolism

Substances

  • Ubiquitin-Protein Ligases
  • Dynamins
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase
  • Dnm1l protein, rat
  • AMP-Activated Protein Kinases
  • Hesperidin
  • hesperetin
  • Prkaa1 protein, rat