Limonene on Regulating Metabolism-related Fatty Liver Disease (MAFLD) and Analysis of TCM Constitution
Condition: Fatty Liver
MeSH terms: Liver Diseases; Fatty Liver
Study type: Interventional
Phase: Early Phase 1

Summary: 
      The prevention and treatment of metabolic-related fatty liver disease (MAFLD) involves many
      fields in preventive medicine and clinical medicine. So far, western medicine has not yet
      completed the elucidation of the mechanism of this type of disease, and there is a lack of
      effective therapeutic drugs.The purpose of this study was to evaluate the effectiveness and
      safety of limonene capsules (marketed product in China) in the treatment of metabolic-related
      fatty liver disease and related lipid-lowering mechanisms.
    

Detailed description: 
      In April 2020, in the famous journal "Journal of Hepatology" in the field of liver disease,
      an internationally renowned liver disease expert group jointly proposed to replace
      non-alcoholic fatty liver disease (NAFLD) with metabolic associated fatty liver disease
      (MAFLD) . The concept of non-alcoholic fatty liver disease (NAFLD) was first proposed by
      Ludwig in 1980. It specifically refers to the excessive deposition of liver fat without
      excessive drinking. It is a type of liver that is closely related to insulin resistance and
      genetic susceptibility. Non-alcoholic fatty liver disease (NAFLD) is China country's largest
      chronic liver disease and the primary cause of abnormal liver enzymes in health examinations.
      It can lead to liver disability and death. It is also closely related to a variety of
      metabolic diseases and the high incidence of colorectal tumors. Western medicine has not yet
      fully elucidated its mechanism, and no drugs have been officially approved for the clinical
      treatment of NAFLD.

      The new MAFLD nomenclature highlights the central role of metabolic factors in causing liver
      fat deposition in this type of liver disease. Traditional Chinese medicine believes that the
      abnormal accumulation of fat in the liver of such fatty liver patients is a pathological
      product of the microscopic loss of water and valley essence. It belongs to phlegm stasis,
      which blocks the liver collaterals. It coincides with the core of the metabolic etiology of
      recent liver disease experts.

      Limonene is widely found in the essential oils of traditional Chinese medicine tangerine
      peel, green peel and other plants. Its taste is sour, sweet and pungent.It is returned to the
      liver and gallbladder meridian. It has an aromatic odor effect.

      A large number of animal and cell experiments in the early stage have shown that limonene can
      inhibit the differentiation of adipocytes (pre-adipocytes) and promote the apoptosis of
      mature adipocytes, which is related to the inhibition of fatty acid synthesis. Toxicity load
      experiments show that limonene has very low toxicity. The accumulation of lipids in the liver
      of mice has a regulatory effect with significantly reducing the content of liver cholesterol
      and triglycerides, and also has a certain effect on lipid metabolism disorders, hyperglycemia
      and other metabolic syndromes. It can alleviate the effects of high-fat diet and N- Efficacy
      of nitro-L-arginine methyl ester-induced resistance to non-alcoholic fatty liver in rats. The
      main indication of limonene capsules (marketed product in China) is liver and gallbladder
      diseases. Traditional Chinese medicine believes that liver and gallbladder are related to
      each other. This comprehensively shows that limonene capsules are promising to be developed
      as a pure Chinese medicine product for the safe and effective treatment of MAFLD.

      However, there has been no clinical evaluation of the clinical efficacy of limonene in the
      treatment of metabolic-related fatty liver disease. As a typical aromatic Chinese medicine,
      the mechanism of limonene in the treatment of fatty liver urgently needs to be revealed by
      modern medicine and molecular biology techniques.

      This study intends to use a randomized, double-blind, placebo-controlled method to evaluate
      the effect of limonene on improving the degree of fat infiltration in patients with
      metabolic-related fatty liver disease (MAFLD), and to evaluate its body mass index BMI, waist
      circumference, waist-to-hip ratio, subcutaneous fat thickness, fat percentage, changes in
      metabolic components, safety,etc. The study also intends to use metabonomics, genomics, and
      molecular biology techniques to study the clinical relationship between metabolites and
      physiological and pathological changes in patients with liver fat infiltration, and to detect
      changes in key proteins and lipid components after drug intervention, which is to reveal
      mechanism on treatment of metabolic-related fatty liver disease by limonene. It is aimed to
      study the difference in the efficacy of limonene for people with different constitutions of
      traditional Chinese medicine (TCM) combined with the analysis of the constitution of TCM, and
      to clarify the modern scientific attributes of TCM therapy. Finally the study will develop a
      safe and efficient drug treatment technology to control liver fat infiltration , and to
      promote the development of clinical disciplines in the treatment of metabolic-related fatty
      liver disease.
    

Intervention name(s): Limonene capsule; Limonene capsules(Placebo)
Intervention type(s): Drug; Drug
Intervention description(s): All the recruiters will be given treatment under the guidance of basic diet. Basic dietary guidelines include high-quality protein and fresh green leafy vegetables. It need to controlled sugar, various sweets and high-calorie foods, frying and other foods with high oil content and foods with high cholesterol content. Limonene capsules group and placebo group were used for treatment. The random number is generated by the central randomization system. All the recruiters were divided into placebo control group and limonene capsule administration group. The numbers will be assigned according to random numbers. In this study, qualified subjects were randomly assigned to the treatment group and the placebo control group at a ratio of 1:1. The drug was administered for 12 weeks, 3 times a day, 5 capsules each time.; Limonene capsules(Placebo)
Other intervention name(s): DAN LENING capsule
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Exploratory Clinical Trial；Randomized Controlled Trial
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Metabolic associated fatty liver disease (MAFLD); Limonene; Efficacy; Safety