2021年11月5日金曜日

The diet medicine is completed! Human dream! Discovered Rubicon, a protein that suppresses fat breakdown (autophagy)! If you can develop a drug that breaks down this Rubicon, you will lose weight.

I quoted it for studying.

http://resou.osaka-u.ac.jp/ja/research/2016/20160913_1


Points of this research result

Autophagy Is a protein that suppressesRubicon Was found to worsen the pathological condition of fatty liver, which is a lifestyle disease, by increasing in the liver when ingesting a high-fat diet.
・ Although the pathogenic mechanism of fatty liver was unknown, autophagy due to increased expression of Rubicon Elucidation that suppression causes fatty deposits in the liver and liver damage
・ Expected to be applied to therapeutic agents for fatty liver targeting Rubicon in the future

Overview

Satoshi Tanaka Graduate Student, Assistant Professor Hayato Hikita, Professor Tetsuro Takehara (Graduate School of Frontier Biosciences, Osaka University) and Tamotsu Yoshimori (Graduate School of Frontier Biosciences, Osaka University) The research group found that increased expression of Rubicon in the liver is the cause of fatty liver (Fig. 1).

It has been reported that autophagy (intracellular degradation mechanism) is suppressed in fatty liver, but the details have not been clarified. The research group found that a high-fat diet increases Rubicon in the liver and suppresses autophagy, which exacerbates the condition of fatty liver. In the future, controlling Rubicon is expected to be applied to the treatment of fatty liver.

The results of this research have been published online in the American scientific journal "Hepatology" since late September.

Fig. 1 Mechanism of fatty liver development A
fat diet increases hepatocyte Rubicon, suppresses lipolysis, and promotes cell death.

Research background

Fatty liver (a disease in which fat accumulates in hepatocytes) caused by excessive nutrition is increasing in developed countries including Japan, and it is said that about 30% of the population suffers from fatty liver. It is a high lifestyle-related disease. Also, part of fatty liverNon-alcoholic steatohepatitis After that, it becomes severe and progresses to liver cirrhosis and liver cancer, so how to suppress the exacerbation of fatty liver is an issue. However, at present, there is no effective drug for treating fatty liver, and it is hoped that the pathophysiology will be elucidated and that it will lead to the development of treatment methods.

So far, it has been reported that autophagy (a mechanism that breaks down intracellular components) is suppressed in fatty liver, but the details have not been clarified. Therefore, the research group focused on Rubicon, a protein that suppresses autophagy, and in human cultured hepatocytes fed with fat and hepatocytes in mice that developed fatty liver in a hypertrophic state, Rubicon and autophagy We investigated the relationship with cell death (apulosis).

Results of this research

The research group found that Rubicon expression was elevated in fat-fed human cultured hepatocytes (HepG2: human liver cancer-derived cells) and mouse hepatocytes fed a high-fat diet (32% fat content, 4 months). We have found that autophagy is suppressed. It also suppresses the expression of this Rubicon (knock outBy doing so, fat accumulation and cell death in the mouse liver are reduced (Fig. 2), and it is clarified that the exacerbation of fatty liver is caused by the decrease in autophagy function through the increased expression of Rubicon. bottom.

The research group also confirmed that Rubicon expression was also elevated in the liver of patients with non-alcoholic steatohepatitis.

Fig. 2 Comparison of liver and liver cells of mice fed a high-fat diet When
the expression of Rubicon was suppressed (knocked out), the size of the liver enlarged by the high-fat diet returned to normal, and the intracellular fat (lower figure, red) ) Accumulation is suppressed.

Impact of this research result on society (Significance of this research result)

Based on the results of this research, it is expected to develop a therapeutic drug that reduces intrahepatic fat in patients and reduces liver damage by targeting Rubicon for fatty liver for which no effective drug treatment has existed until now. .. This is also expected to suppress the onset of non-alcoholic steatohepatitis and liver cancer, which become more severe from fatty liver.

In addition, there have been several known congenital diseases (genetic diseases) that develop due to decreased autophagy due to gene mutation, but this study is an acquired environmental factor (this time, high-fat diet intake). This is the first example of how autophagy is reduced and the disease develops. Health problems caused by overnutrition are one of the most important issues in modern society, and this point is also drawing attention.

Remarks

The results of this research have been published in the American scientific journal "Hepatology" (online) since late September 2016.
[Title] Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease.
[Author] Satoshi Tanaka   , Hayato Hikita   , Tomohide Tatsumi   , Ryotaro Sakamori   , Yasutoshi Nozaki   , Sadatsugu Sakane   , Yuto Shiode   , Tasuku Nakabori   , YoshinobuSaito   , Naoki Hiramatsu   , Keisuke Tabata   , Tsuyoshi Kawabata   , Maho Hamasaki   , Hidetoshi Eguchi  , Hiroaki Nagano   , Tamotsu Yoshimori  2 *  and Tetsuo Takehara  1 *
1. Osaka University Graduate School of Medicine Gastroenterology
2. Osaka University Graduate School of Medicine Genetics
3. Osaka University Graduate School of Medicine Gastroenterology Science
(* responsible author)

This research is a network of the Innovative Advanced Research and Development Support Project (AMED-CREST) ​​of the Ministry of Education, Culture, Sports, Science and Technology and the Japan Medical Research and Development Organization (AMED). "Creation of technology for realizing optimal medical care based on understanding" Research and development subject in the research and development area (R & D summary: Ryozo Nagai) It was carried out as part of "Establishment" (Research and Development Representative: Yasushi Yoshimori). This R & D area was transferred from the Japan Agency for Medical Research and Development (JST) with the establishment of the Japan Agency for Medical Research and Development in April 2015.

In addition, this research was conducted by Hiroaki Nagano, former associate professor (at that time, Osaka University Gastroenterology, now Yamaguchi University School of Medicine, Department of Gastroenterology and Oncology), Hidetoshi Eguchi (Osaka University Gastroenterology), etc. It was carried out with the cooperation of.

Researcher's comment

<Professor Yoshimori> Since
I discovered Rubicon as a protein that suppresses autophagy, I have been interested in the relationship between this protein and diseases and have been researching it. This is the first report of a disease caused by Rubicon. Many diseases associated with autophagy failure have been reported in addition to fatty liver. Some of these may actually be caused by Rubicon.

<Professor Takehara>
We have proved that persistent cell death in the liver causes fibrosis and carcinogenesis in the liver. Elucidation of the mechanism of hepatocellular death is the key to controlling the progression of chronic liver disease. Here, it was revealed that suppression of autophagy by Rubicon is involved in the progression of hepatocellular death in fatty liver. At the same time, it was shown that it affects fat metabolism and is involved in the formation of fatty liver itself. We would like to connect the results of this research to the treatment of fatty liver, which is the most frequent liver disease.

<Tanaka graduate student>
It has been shown that the functional decline of autophagy is involved in the pathogenesis of rare diseases such as genetic diseases, but the number of patients has been increasing in recent years for non-alcoholic fatty liver disease. It was shown to contribute to the pathogenesis of (NAFLD). Furthermore, from the viewpoint of molecular mechanism, we discovered that the Rubicon protein discovered by Professor Tamotsu Yoshimori of our university plays an important role. I would like to lead to the development of new therapeutic agents for non-alcoholic steatohepatitis (NASH), for which there is no effective therapeutic agent yet.

Reference URL

Graduate School of Medicine Gastroenterology
http://www.med.osaka-u.ac.jp/pub/gh/index.html

Glossary

Autophagy

A mechanism that wraps proteins and structures existing in cells with a double membrane and fuses with lysosomes (organelles with various digestive enzymes) to decompose the wrapped contents. When autophagy begins, a sequestering membrane appears in the cytoplasm. The isolation membrane stretches to surround the degradation target and form autophagosomes. Autophagosomes fuse with lysosomes to form autophagosomes, and digestive enzymes in the lysosomes decompose the substances to be decomposed.

Rubicon

(Rubycon; Run domain Beclin-1 interacting And cysteine-rich containing protein):

A protein that suppresses autophagy, discovered in 2009 by Professor Yoshimori and others of this research group. It is known that the autophagy function decreases when the fusion of autophagosomes and lysosomes, which is the final step of autophagy, is suppressed and the intracellular Rubicon increases.

Non-alcoholic steatohepatitis

(Non-alcoholic steatohepatitis: NASH):

Fatty liver disease is a general term for pathological conditions in which fat (neutral fat) is deposited in hepatocytes and causes liver damage. Non-alcoholic fatty liver disease (NAFLD) is a fatty liver disease with no clear history of drinking (ethanol equivalent intake of 30 g for men and less than 20 g / day for women). In recent years, NAFLD is the most common chronic liver disease, affecting about 30% of the population in developed countries and increasing. NAFLD is divided into simple fatty liver with a good prognosis and progressive non-alcoholic steatohepatitis (NASH). NASH accounts for 10-20% of all NAFLD, and is accompanied by inflammation and fibrosis in addition to fatty liver, leading to cirrhosis and hepatocellular carcinoma as it progresses.

knock out

Knockout mouse:

Genetically modified mice produced by genetic engineering so that expression of a specific gene does not occur.

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