Preventive Effect of Citrus aurantium Peel Extract on High-Fat Diet-Induced Non-alcoholic Fatty Liver in Mice

Biol Pharm Bull. 2019;42(2):255-260. doi: 10.1248/bpb.b18-00702.


Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation, which is the most common form of chronic liver disease. Multiple clinical studies using natural compounds such as flavonoids have been conducted to treat NAFLD. In the present study, the pharmacological effect of Citrus aurantium L. (Rutaceae) peel extract (CAE), which contains over 27% of polymethoxyflavone nobiletin, on NAFLD was evaluated using a high-fat diet (HFD) animal model susceptible to developing NAFLD. C57BL/6 mice were fed an HFD (60% kcal of energy derived from fat) for 8 weeks to induce obesity. Obese mice were randomly allocated to four groups of eight mice each (HFD alone, HFD with silymarin, HFD with 50 mg/kg CAE, and HFD with 100 mg/kg CAE). After 8 weeks of treatment, all mice were euthanized, and plasma and liver tissues were analyzed biochemically and histopathologically. The results indicate that CAE treatment significantly reduced HFD-induced NAFLD, as shown by decreased serum lipid index and prevented liver histopathology. The expression of genes involved in lipid synthesis including free fatty acid (FFA), peroxisome-proliferator-activated receptor γ (PPAR-γ), sterol receptor element binding protein 1c (SREBP-1c), and fatty acid synthesis enzyme was suppressed by CAE treatment. Moreover, compared to untreated mice, CAE-treated HFD mice showed decreased pro-inflammatory cytokine expression. These results demonstrated that CAE prevented HFD-induced NAFLD by reducing plasma levels of triglyceride and cholesterol and de novo lipid synthesis.

Keywords: cholesterol; polymethoxyflavone; triglyceride.

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Citrus / chemistry*
  • Diet, High-Fat
  • Flavonoids / pharmacology*
  • Lipid Metabolism / drug effects
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • NF-E2-Related Factor 2 / metabolism
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / pathology
  • Non-alcoholic Fatty Liver Disease / prevention & control*
  • PPAR gamma / biosynthesis
  • PPAR gamma / genetics
  • Plant Extracts / pharmacology
  • Protein Kinases / metabolism
  • Random Allocation
  • Silymarin / pharmacology
  • Sterol Regulatory Element Binding Protein 1 / biosynthesis
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • fas Receptor / metabolism


  • Fas protein, mouse
  • Flavonoids
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • PPAR gamma
  • Plant Extracts
  • Silymarin
  • Sterol Regulatory Element Binding Protein 1
  • fas Receptor
  • Protein Kinases
  • AMP-activated protein kinase kinase