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Liver activation

& Liver fat reduction

Presented at;

The 4th meeting of the Public Interest Incorporated Foundation of Science and Technology Interaction “Development and application of new fatty acid analysis method aimed at extending healthy longevity” (July 28 2017, Nagoya, Japan)

To be presented at;

The 20th Scientific Meeting of the Japanese Society of Anti-Aging Medicine (2020, Japan),

The 68th Annual Meeting of the Japanese Society for Food Science and Technology (August 2021, Fukuoka, Japan)

Joint Research Partner : O’Atari Inc.

Joint Research Partner : Professor Teruyuki SEINO, Department of Material and Environmental Engineering, Hakodate National College of Technology

 

 

Development motivation

There are many people who like to drink alcohol including myself. Many people say that “Drinking alcohol relaxes us and relieves our stress.” It also has many benefits, such as making it easier to communicate [1].

However, when you drink alcohol, it has an appetizing effect, and neutral fat accumulates in the liver to cause obesity, thus fatty liver is easy to develop. On the other hand, alcohol itself activates the function of making neutral fat in the liver, so it induces fatty liver, too. Fatty liver is known to cause hepatitis and progress to cirrhosis and then to liver cancer (Fig. 1) [2]. Stress, lack of exercise, and smoking are also major factors for causing fatty liver. For this reason, do we relieve stress with drinking alcohol or can we relive stress without drinking alcohol???

A friend of mine who loves alcohol recently developed liver cancer from fatty liver, and I decided to start researching about it.

 

Fig. 1  Progression from fatty liver to liver cancer

 

 

 

What is fatty liver?

The liver breaks down sugar and synthesizes and accumulates neutral fat as an energy source (Fig. 2). However, the accumulation of more than 30% of fat in the liver is called fatty liver. Fatty liver occurs due to overeating (obesity) or excessive drinking [3]. Fatty liver is also caused by stress, smoking, and diabetes. It is classified into two types: alcoholic fatty liver and non-alcoholic fatty liver [2, 3].

Alcohol is metabolized and detoxified in the liver. At this time, it becomes energy and fatty acid, that becomes neutral fat. In this process, fat is accumulated because fat is not burned in the liver and also because it activates the production of neutral fat from sugar. In addition, drinking alcohol increases appetite and increases fat accumulation in the liver, therefore excessive drinking causes alcoholic fatty liver [2].

Non-alcoholic fatty liver is caused by obesity, diabetes, and other conditions that impair insulin secretion and make the liver more likely to store fat [3].

As fatty liver progresses, it causes steatohepatitis, inflammation triggering fibrosis of the liver, cirrhosis, genetic mutations leading liver cancer, and death [2, 3]. This is partly because fatty deposits in the liver cause mutations in the mitochondria in liver cells [4, 5].

 

Fig. 2  Liver function

 

 

 

How to resolve fatty liver?

To resolve fatty liver, it is important to save drinking, eating and to do exercise. When stress is accumulated without drinking alcohol, fatty liver is also caused. I can drink alcohol if there are any other way to stop fatty liver… So, I searched about it, but unfortunately there was no such medicine. Next, when I searched for foods, there were reports about extractives (extract) and ingredients of garlic, bitter gourd, ginger, lychee, Korean ginseng, and Korean five leaves (Pinus densiflora) [6]. We focused on ginger, that had a long diet and was submitted for clinical trials [7 -9].

 

 

 

What is ginger?

Ginger has been cultivated in tropical Asia since 650 B.C., and has a long history of healthy eating habits as a crude drug, herbal medicine, and as a cooking ingredient such as condiments [10].

The following efficacies of ginger have been reported [10 -15]: nausea and vomiting control, digestion promotion, lipid lowering (Improvement of blood lipids and anti-fat accumulation), antihypertension (cardiovascular protection), anti-inflammatory (analgesics, cough suppressants, and anti-arthritis), anti-oxidant, anti-cancer, energy consumption promotion (sweating, heat production, blood circulation improvement, cold sensitivity improvement, promotion of body fat combustion), glucose absorption reduction, anti-obesity, anti-diabetes, immune enhancement, anti-microbial, diuresis promotion, and neuroprotection. Active ingredients include gingerol abundant in fresh ginger, shogaol abundant in heated and dried ginger, gingerone, quercetin, and essential oils [15].

Side effects of ginger include heartburn, diarrhea, and irritation in the mouth [15].

Ginger is studied in clinical trials to reduce liver fat without analysis of the ingredients of ginger [7].

 

 

 

What is the active ingredient of ginger to reduce liver fat?

Activation of liver metabolism (mitochondria) and breakdown of fat (lipid), promotion of β-oxidation of lipids, are important in reducing liver fat.

For these functions, ginger has been reported to contain two ingredients, 6-gingerol (abundant in fresh ginger), and 6-shogaol (abundant in heated ginger), together with essential oil [8, 16, 17, 18]. However, a paper denied 6-gingerol efficacy [17].

So, we used liver cells to test 6-gingerol and 6-shogaol for liver activation and fat reduction.

 

 

 

Examination of liver activation and liver fat reduction by 6-gingerol and 6-shogaol

Ginger’s ingredients act directly on liver cells in the liver, and then they are metabolized by the liver, and the metabolized ingredients act on liver cells. For this reason, we monitored mitochondrial activation in liver cells using our proprietary HP-SPR-3D method correlating to clinical results [19]. Cells were cultured in three dimensions to measure changes in fat content.

As a result, at 100nM, 6-gingerol exhibited apoptotic (cell death) toxicity both before and after metabolism in the liver, and 6-shogaol exhibited enhanced metabolic activity in the liver, about 2 times higher after metabolism than before metabolism (Figs. 3 and 4). At 1000nM 6-shogaol, apoptotic toxicity was observed before metabolism, and detoxification was observed after metabolism by promoting metabolic activity. At 100nM, 6-shogaol reduced liver fat (fluorescent area) by approximately 20% (Fig. 5).

From these results, 6-gingerol, a raw ginger ingredient, did not activate liver metabolism or decrease liver fat. Although 6-shogaol, a heated ginger ingredient, activated liver metabolism and decreased liver fat. However, excessive intake of 6-shogaol was found to have adverse effects.

Fig. 3  Liver activation effect of 6-gingerol

Fig. 4  Liver activation effect of 6-shogaol

Fig. 5  Effect of liver fat reduction by 6-shogaol

 

 

 

How to maximize the ability of ginger to reduce fatty liver?

Ginger root (ginger rhizome) is a baby of ginger. Ginger produced in autumn passes through winter, and when spring comes, it awakens from sleep, shoots and grows. For this reason, the ingredients of ginger are hard to dissolve in water so that they do not flow out even if it rains when ginger is sleeping. When ginger wakes up from sleep, ginger changes the ingredients into a form that dissolves easily in water and use them to grow [20].

Ginger root produces sugar, amino acids, minerals, hormones, and even substances that boost immunity against diseases after the buds have sprouted.

The same is true in humans, where substances that are difficult to dissolve in water need to be converted into water soluble substances in the body, making them less efficient and possibly more toxic [21].

Extractives and extracts are not bad, but I wanted to take them as food if possible.

 

 

 

Any ginger is OK?

Only organic ginger grown in Shimabara, Nagasaki Prefecture, Japan was purchased from cooperative farmers and used. Therefore, we carefully select safe and delicious food.

 

 

 

How do we wake ginger up?

The ingredients become uneven if ginger is not awakened at the same time, so gingers are asked to wake up rapidly and synchronizedly in 1-2 days using our proprietary Grandir recipeTM to make the ingredients have the baby’s vitality.

Then they were sliced, steamed and dried (Fig. 6). As a result, the 6-shogaol content of awakened ginger was approximately 6 times higher than that of fresh ginger (unprocessed) and approximately 1.5 times higher than that of not awakened ginger (Ultra Ginger = steamed and dried ginger) (Fig. 7).

Fig. 6  Experimental scheme

Fig. 7  6-Shogaol content percentage

 

 

 

Liver metabolic activation and liver fat reduction effects of rapid and synchronized dormancy broken (RSDB) ginger rhizomes on humans

Using human liver cells, we monitored mitochondrial activation by our proprietary HP-SPR-3D method [19], that correlates to clinical results, for the metabolic activation of liver cells by rapid and synchronized dormancy broken (RSDB) ginger rhizomes, assuming oral administration (eating). Cells were also cultured in three dimensions to measure changes in fat content (Fig. 6).

As a result, liver metabolism was activated in a concentration-dependent manner, and a decrease in liver fat was observed (Fig. 8). We can expect a fat reduction at least 10%.

Fig. 8   Effect of liver fat reduction by rapid and synchronized dormancy broken (RSDB) ginger rhizomes

 

 

 

Rapid and synchronized dormancy broken (RSDB) ginger rhizomes

We have succeeded in developing safe, reliable, and highly functional food products without extraction or concentration of ingredients. Youthfulness and healthiness are declined by aging. The vital power of the baby ginger works on the body’s natural power to help keep it in good condition.

We are currently continuing our research, so we will update the data as soon as it comes out.

 

 

References

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[2] O’shea, R. S., Dasarathy, S., McCullough, A. J., & Practice Guideline Committee of the American Association for the Study of Liver Diseases and the Practice Parameters Committee of the American College of Gastroenterology. (2010). Alcoholic liver disease. Hepatology51(1), 307-328.

[3] Mostafa, M., Abdelkader, A., Evans, J. J., Hagen, C. E., & Hartley, C. P. (2020). Fatty liver disease: A practical approach. Archives of Pathology & Laboratory Medicine144(1), 62-70.

[4] García‐Ruiz, C., & Fernández-Checa, J. C. (2018). Mitochondrial oxidative stress and antioxidants balance in fatty liver disease. Hepatology Communications2(12), 1425-1439.

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[7] Rahimlou, M., Yari, Z., Hekmatdoost, A., Alavian, S. M., & Keshavarz, S. A. (2016). Ginger Supplementation in Nonalcoholic Fatty Liver Disease: A Randomized, Double-Blind, Placebo-Controlled Pilot Study. Hepatitis monthly16(1), e34897. https://doi.org/10.5812/hepatmon.34897

[8] Liu, C. T., Raghu, R., Lin, S. H., Wang, S. Y., Kuo, C. H., Tseng, Y. J., & Sheen, L. Y. (2013). Metabolomics of ginger essential oil against alcoholic fatty liver in mice. Journal of Agricultural and Food Chemistry61(46), 11231-11240.

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[14] Miyamoto, M., Matsuzaki, K., Katakura, M., Hara, T., Tanabe, Y., & Shido, O. (2015). Oral intake of encapsulated dried ginger root powder hardly affects human thermoregulatory function, but appears to facilitate fat utilization. International Journal of Biometeorology59(10), 1461-1474.

[15] Mao, Q. Q., Xu, X. Y., Cao, S. Y., Gan, R. Y., Corke, H., Beta, T., & Li, H. B. (2019). Bioactive Compounds and Bioactivities of Ginger (Zingiber officinale Roscoe). Foods (Basel, Switzerland)8(6), 185. https://doi.org/10.1186/s12885-017-3706-6

[16] Isa, Y., Miyakawa, Y., Yanagisawa, M., Goto, T., Kang, M. S., Kawada, T., Morimitsu, Y., Kubota, K., & Tsuda, T. (2008). 6-Shogaol and 6-gingerol, the pungent of ginger, inhibit TNF-α mediated downregulation of adiponectin expression via different mechanisms in 3T3-L1 adipocytes. Biochemical and Biophysical Research Communications373(3), 429-434.

[17] Suk, S., Seo, S. G., Yu, J. G., Yang, H., Jeong, E., Jang, Y. J., Yaghmoor, S. S., Ahmed, Y., Yousef, J. M., Abualnaja, K. O., Al-Malki, A. L., Kumosani, T. A., Lee, C. Y., Lee, H. J., & Lee, K. W. (2016). A Bioactive constituent of ginger, 6-shogaol, prevents adipogenesis and stimulates lipolysis in 3T3-L1 adipocytes. Journal of Food Biochemistry40(1), 84-90.

[18] Lai, Y. S., Lee, W. C., Lin, Y. E., Ho, C. T., Lu, K. H., Lin, S. H., Panyod, S., Chu, Y. L., & Sheen, L. Y. (2016). Ginger essential oil ameliorates hepatic injury and lipid accumulation in high fat diet-induced nonalcoholic fatty liver disease. Journal of Agricultural and Food Chemistry64(10), 2062-2071.

[19] Johzuka, J., Ona, T., & Nomura, M. (2018). One hour in vivo-like phenotypic screening system for anti-cancer drugs using a high precision surface Plasmon resonance device. Analytical Sciences34(10), 1189-1194.

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[21] Kigel, J. (Ed.). (1995). Seed development and germination (Vol. 41). CRC press.

[22] Gibson, G. G., & Skett, P. (2013). Introduction to drug metabolism. Springer.