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👩‍🎓 | Elucidation that inhibition of glutamine metabolism eliminates aging cells and improves the aging phenomenon


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Elucidation that inhibition of glutamine metabolism eliminates senescent cells and improves the aging phenomenon

 
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In addition, administration of a GLS1 inhibitor to age-related disease model mice alleviated the symptoms of obese diabetes mellitus, arteriosclerosis, and non-alcoholic fatty liver.
 

Groups such as the University of Tokyo, Kyushu University, Niigata University, Keio University, and National Center for Longevity Medical Research have glutamine metabolism ... → Continue reading

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Fatty liver

Fatty liver(Shibokan,English: fatty liver) IsliverToNeutral fatRefers to the state in which is abnormally accumulated.

When using a tissue sampleHepatocytesFat vacuoles can be seen inside.In summary, for some reason, the processing of fat metabolism has fallen into a situation where the processing of fat metabolism cannot keep up, so that fat accumulates in the hepatocytes like oil droplets and the hepatocytes are swollen.

Even a normal liver has about 5% fat by wet weight, but 30% or more of lipids (mainly triglycerides) are excessively accumulated.[1].Body mass index(BMI) Most people with a body mass index of 30 or more have been reported to have fatty liver.[2]..In rare cases, fatigue and slight discomfort in the abdomen may be felt, but there are no characteristic subjective symptoms, and it occurs even in non-obese people and is regarded as a mere complication of liver damage.CirrhosisUnlike the above, the liver is still in a reversible state, so doctors' interest was low and it was clinically neglected, and it was pointed out that clinical research and countermeasures were insufficient.[3]が、研究の進展により肥満、内臓脂肪蓄積、インスリン抵抗性などの因子が加わることで心血管疾患の発症リスクが相乗的に高まることが報告されている[4].

ガ チ ョ ウ,duckA high-class ingredient that enlarges the liver of the liver by forced fatteningFoie gras"And rarelyChickenThe "white liver" found in hens is actually fatty liver.For this reason, fatty liver is commonly referred to asFoie gras stateIt may be likened to being.

Epidemiology

Globally, alcoholic steatohepatitis caused by drinking is a typical example of fatty liver.[5][6]..In Japan, women's severe alcoholic steatohepatitis is on the riseLow-malt beer,WineAlthough it may be seen as the effect of the boom, the number of fatty patients is increasing in Japan despite the decrease in alcohol consumption.[7][8].. According to a survey conducted in Miyagi prefecture from 1991 to 1998, the frequency of fatty liver doubled in 16.6 years from 32.6% to 7%.[8]..According to a survey in the United States, 13% of children as well as adults have fatty liver, and 38% of obese children have fatty liver.[9][4].

There are various causes of fatty liver, but since it is a non-progressive (reversible) change, it returns to normal when the cause is removed.[3]..Therefore, fatty liver itself is not regarded as a disease.[3]..However, fatty liver can cause chronic inflammation of the liver and cause liver dysfunction, and is an irreversible lesion if left untreated.Cirrhosis,Liver cancerAlso causes[10]..In particular, non-alcoholic steatohepatitis among fatty livers in Japan accounts for about 30% of adult medical examinations (male-40%, female-17%)[11]) Is affected[12][13].

Japanese have a high prevalence of the mutant β-adrenergic receptor (Trp64Agr) known as a sparing gene, and the risk of developing non-alcoholic fatty liver disease increases 64-fold when having Trp2.4Agr.[2]..In addition, having a PNPLA3 gene polymorphism or a Val175Met gene polymorphism associated with choline deficiency is likely to cause fatty liver.[2].

Clinical picture

Although fatty liver itself is not regarded as a disease and is often neglected[3],obesity,Dyslipidemia,Diabetes mellitusSuch asLifestyle-related diseasesIt may occur in close relation to.On the other handComplete medical checkupOf the examinees BMI It has been reported that about 25% of people who are non-obese and have no abnormal values ​​of ALT (GPT) or ALP (GOT) in liver function tests have fatty liver findings.[14]..However, in the Asia-Pacific region, 15% to 21% of patients with non-alcoholic fatty liver disease (NAFLD) are associated with obesity.[15][4]..In addition, long-term diabetic patients may develop cirrhosis from fatty liver without noticing it.[12].

In addition, while overnutrition may cause fatty liver,anorexia[16]And undernutrition due to inappropriate dietStarvationIt is also known that fatty liver may occur even if the liver continues for a long period of time.[10].

stage

As fat accumulation progresses, hepatocytes gradually become fibrotic.The stages of fibrosis are classified as follows:[17].

Stage 1Partial or widespread fibrosis in the central lobe
Stage 2Partial or widespread portal vein fibrosis in addition to Stage 1
Stage 3Bridging fibrosis
Stage 4Cirrhosis

As an index that can predict the progress of fibrosis FIB-4 index There is[18][19].

  • FIB-4 index calculation method
( AST age ) ( Platelet count )
Note: AST and ALT are IU / L.Platelet count is 109/ L (0.1 / μL)
  • Judgment
With 2.67 or higher, liver fibrosis is certain and NASH is likely.Liver biopsy required[20]
Even if the ALT value is within the standard value, if it is NAFLD, it is 1.659 or more (≧), and there is a possibility of liver fibrosis.[21]
1.3 or less, no liver fibrosis.follow-up[20]

Cause

The most common cause, especiallyethanolHeavy drinking of more than 20 (g / day) in conversion is oftenAlcoholic fatty livercause.
obesity,Insulin resistance-Neutral fatHigh pricecarbohydrateOverdose
  • Drug
Acute fatty liver of pregnancy(AFLP) ・HELLP syndromeWait
  • Abnormal nutrition / eating disorders (excessive- obesity, Shortage- hunger,anorexia[16], After small bowel surgery[23]), Abnormal glucose metabolism[24]

Diagnosis

Diagnosis is made by several tests and interviews.

NAFLD / NASH diagnostic chart[25]
Fatty liver
Liver disorder
HBs antigen, HVC antibody
Various autoantibodies, etc.
ThereViral liver disease,
Autoimmune liver disease
NoneDrinking historyThereAlcoholic liver disorder
NoneNAFLDBy live liver examination
Pathological diagnosis
Non-alcoholic steatohepatitis
(NASH)
Non-alcoholic fatty liver
NAFL
  • "Japanese Society of Gastroenterology NAFLD / NASH Clinical Practice Guidelines 2014"[25]Quoted and modified

Blood test

Hepatitis B virus(HBsAg),Hepatitis C virus(HVC antibody), various autoantibodies (Autoimmune hepatitis), Etc. to distinguish the underlying disease.Alanine aminotransferase (ALT) andAspartate aminotransferaseFatty liver cannot be diagnosed based on the results of the (AST) blood test.The reason is that in fatty liver caused by viral hepatitis, ALT and AST sometimes rise above 100 (IU / L), whereas in non-alcoholic fatty liver, the increase in ALT and AST is small.[26]..Also, in non-alcoholic steatohepatitis (NASH), when the fibrosis of hepatocytes progresses and the number of normal hepatocytes decreases, the values ​​of ALT and AST rather decrease.[26].

InspectionNormal valueIn fatty liver?
AST (GOT)10-40 IU / LMild rise.ALT> AST for overnutrition
ALT (GPT)5-35 IU / LAST> ALT for alcoholic
γ-GTP50 IU / L or lessHigher in alcoholic fatty liver
Cholinesterase186-490 IU / LRise due to overnutrition
Total cholesterol120-220 mg / dlGet higher
Neutral fat50-150 mg / dlGet higher
platelet13.-37.9 / µL[27]20 / µL or less[28]

General South Tohoku Hospital materials[29]More quoted and modified.

Image inspection

  • Echo examination
    "Hepatobiliary contrast"Hepatorenal contrast" (liver echoes more than kidney) and "Liver-spleen contrast"Elevation" (liver echoes higher than spleen) is seen.There is also deep attenuation.The liver is swollen and the lower right lobe of the liver is on the rightKidneyIt may be located caudal to the lower pole.Ultrasound is incident diagonallygall bladderOn the wall, the wall becomes obscured "fatty boundless signIs also seen.
    If there are areas with high or low fat deposition in the localized area,tumorIt is necessary to distinguish.The distinguishing point is the presence or absence of a normal vascular structure such as the portal vein.
  • CT
    Evaluate liver damage and fatty degeneration based on morphology.With fatty degeneration, the signal intensity of the vasculature and parenchyma may be reversed from that of the normal liver (the liver parenchyma becomes a rather low absorption image).
  • MRI

Pathological examination

Liver biopsyHistopathological findings in.BasicallyHepatocytesFatty degeneration is observed.

  • Alcoholic fatty liver
  • Non-alcoholic fatty liver
Diagnostic criteria

Pathological diagnosis (NAS: NAFLD Activity Score) by scoring according to the table below may be performed to reduce the difference in judgment of observers and the difference between facilities.[25].

NAS (NAFLD Activity Score)
ItemdegreeScore
Liver fatteningLess than 5%0 points
5 ~ 33%1 points
33 ~ 66%2 points
66% or more3 points
Inflammation in the lobulesNo lesion0 points
Less than 200 lesions in a 2x field of view1 points
200-2 lesions with a 4x field of view2 points
200 or more lesions with a 4x field of view3 points
Balloon-like changes in hepatocytesNone0 points
A few balloon-like degenerated cells1 points
Numerous balloon-like degenerated cells2 points
DiagnosisTotal
Fatty liver (NAFL)0-2 points
Borderline NASH3-4 points
Non-alcoholic steatohepatitis NASH0-8 points

In addition, the following Younossi diagnostic criteria may be used together.[25].

  1. In addition to hepatocyte fattening (of any degree), central lobular hepatocyte centrilobular ballooning and Mallory-Denk body are observed.
  2. In addition to hepatocyte fattening, pericellular / perisinusoidal fibrosis or bridging fibrosis is observed.

If the above 1. or 2 are satisfied, it is defined as NASH.

Pathology

CarbohydratesSugarIs decomposed into glucose and consumed in biological activities, but the surplus is synthesized into triglycerides and accumulated in hepatocytes.Can be broken down by sugarfructoseShows dose-dependent hepatotoxicity.Fructose is metabolized only in the liver.The reason for this is that fructose has a higher ring-opening rate than glucose (about 10 times higher).Saccharification reactionBecause it is easy to use[30]), The toxicity to the living body is much higher than that of glucose.For the purpose of quickly eliminating this toxicityliverTreats fructose preferentially over glucose[31]..Fructose is found in the liver and skeletal muscleInsulin resistancecause.When insulin resistance develops, from the pancreasInsulinSecretion is promoted.Due to excess insulinHyperinsulinemiaCauses various organ disorders.For exampleDyslipidemiaAnd cause liver inflammation[32][33].

On the contrary, even when the starvation state of the living body continues for a long period of time due to, for example, anorexia nervosa, fat may accumulate in hepatocytes and become fatty liver.

In fatty liver, serumFerritinIs often seen, and in non-alcoholic steatohepatitis including non-alcoholic steatohepatitis (NASH) among fatty livers, in liver tissueExcessive ironIs considered to be an exacerbating factor for liver damage[34].

治療

  • Alcoholic fatty liverIf,ProhibitionSymptoms improve within 6 weeks.If necessary, improve your eating habits.In addition, it should be notedCirrhosisBecause the liver in the state of fatty liver is reversible[35]Patients may not be abstaining from alcohol for a lifetime, but may be able to temporarily abstain from fatty liver until it returns to normal liver.After the liver is diagnosed as normal, moderate drinking that does not cause recurrence of fatty liver can be tolerated.On the contrary, if you take measures to drink alcohol despite having alcoholic fatty liver, it will progress to alcoholic hepatitis and further to alcoholic cirrhosis, and it will not be a temporary abstinence but a lifetime. No alcohol is required.Because cirrhosis is an irreversible liver lesionLife extension treatmentAlthough it can only be done, drinking alcohol promotes the progression of cirrhosis, and abstinence leads to life extension.[36].
  • With obesityNon-alcoholic steatohepatitisIf,dietBasically, improve eating habits such as snacks and eat habits at night.[37]..Michael Pagliassotti, a professor at Colorado State University, bred the laboratory animals with sugar for 20% of their energy intake, and after a few months the laboratory animals developed fatty liver and developed insulin resistance.It is reported that fatty liver disappeared rapidly and insulin resistance disappeared when sugar was stopped.[32][37].
  • If the cause is anorexia or a diet that reduces protein intake, the main source of calories is often excess carbohydrates and sugars (low-protein-high-carbohydrate), but protein-based (high). It is improved by changing to a diet (protein-low carbohydrate).
  • Diet points[37]
  1. Energy
    • 25-35kcal / kg days, protein 1.0-1.5g / kg days
  2. Distribution of 3 major nutrients
    • 20-25% protein, 15-20% fat, 60% sugar

Anti-fatty liver vitamin-like substance

Sugar alcoholThere are 1 types ofInositolIs not generally classified as a vitamin, but is listed as one of the vitamin-like substances that have similar effects to vitamins.[38]..As one of the actions of this inositol, it is said that there is also an action that makes it difficult for fatty liver to occur.[39].

footnote

  1. ^ Masao Saito, Seiko Yagyu, Yasuko Hattori and others,Study on fatty liver in health checkup examinees "Journal of Japanese Hygiene" 1989, Vol. 44, No. 5, p.953-961, two:10.1265 / jjh.44.953
  2. ^ a b c Keiko Miyamoto, Masafumi Ono, Toshiharu Nishihara,Disease-related genes for non-alcoholic fatty liver disease "Journal of the Japanese Society of Gastroenterology" 2013 Vol. 110 9 p.1597-1601, two:10.11405 / nisshoshi.110.1597
  3. ^ a b c d Masao Saito, Takashi Otsuka, Rei Takahashi, Nobuo Okamoto,Study on the transition of fatty liver and its pathogenic factors "Gastrointestinal mass examination" 1993 Vol. 31, No. 3, p.26-32, two:10.11404 / jsgcs1982.31.3_26
  4. ^ a b c Yuji Ogawa, Kento Imajo, Masato Yoneda and others, "NAFLD epidemiology and pathology update"Journal of the Japanese Society of Gastroenterology" 2014 Vol. 111, No. 1, p.14-24, two:10.11405 / nisshoshi.111.14
  5. ^ Tadashi Doi, Shingo Tanaka, Yasuhiro Sato, etc.[Original] Effect of alcohol intake on the frequency of fatty liver disease "Liver" 2010 Vol. 51, No. 9, p.501-507, two:10.2957 / kanzo.51.501
  6. ^ Yoshiyuki Yamagishi, Shinzo Kato, "Alcoholic Liver Disorder" "medicina." Vol. 43, No. 12, 2006/11/30, two:10.11477 / mf.1402101510
  7. ^ Toshiharu Nishihara, Saburo Onishi,New developments in NASH (non-alcoholic steatohepatitis) "Liver" 2003 Vol. 44, No. 11, p.541-545, two:10.2957 / kanzo.44.541
  8. ^ a b Hiroyoshi Onodera, Katsuaki Ukai, Takao Iwasaki and others,Changes in fatty liver frequency in medical examinations using ultrasonography "Health Medicine" 2000 Vol. 15, No. 3, p.211-214, two:10.11320 / ningendock1986.15.211
  9. ^ Day CP, James OF: Steatohepatitis: a tale of two "hits"? Gastroenterology 114; 842-845: 1998
  10. ^ a b Takato Ueno "What kind of disease is fatty liver and steatohepatitis?(The Japanese Society of Gastroenterology)
  11. ^ Kumiko Totsuka, "Relationship between eating habits and the onset of lifestyle-related diseases: Examination using existing human dock dataUniversity of Tsukuba Dissertation 12102 Ko No. 7849, hdl:2241/00143977
  12. ^ a b Fourth complication of diabetes "cirrhosis derived from fatty liver" Nikkei Medical Article: June 2017, 6
  13. ^ Hiroyoshi Onodera, Takao Iwasaki, Daisuke Shibuya, etc.Examination of changes over time in fatty liver and blood biochemical test values ​​in fatty liver cases by ultrasound examination "Health Medicine" 2001 Vol. 16, No. 2, p.157-161, two:10.11320 / ningendock1986.16.157
  14. ^ Kazunobu Otsuki,Relationship between fatty liver and lifestyle-related diseases by ultrasonic diagnosis in non-obese people "Journal of Japan Gastroenterological Mass Examination Society" 2002, Vol. 40, No. 6, p.542-546, two:10.11404 / jsgcs2000.40.6_542
  15. ^ Liu CJ: Prevalence and risk factors for non-alcoholic fatty liver disease in Asian people who are not obese. J Gastroenterol Hepatol 27; 1555-1560: 2012
  16. ^ a b Yoshiko Saito, Toshio Naito, Junko Kukino and others,Developed in a very low weight woman due to eating disordersCampylobacter fetus A case of sepsis "Journal of the Japanese Association of Infectious Diseases" 2004 Vol. 78, No. 1, p.70-75, two:10.11150 / kansenshogakuzasshi1970.78.70
  17. ^ Yoshihiro Kamada, Hidetomo Miyoshi, Tetsuro Takehara,NAFLD diagnosis and test method update "Journal of the Japanese Society of Gastroenterology" Vol.111 (2014) No.1 p.25-34, two:10.11405 / nisshoshi.111.25
  18. ^ Nobuyuki Kobayashi, Takashi Tsuzuki, Tomoko Manzo, et al.[Original] Changes in liver fibrosis index FIB4 Index over time in cases of fatty liver"Ningen Dock" 2014 Vol. 29, No. 1, p.34-41, two:10.11320 / ningendock.29.34
  19. ^ Information on FIB-4 index calculation site (provided by EA Pharma) (for medical professionals) Japanese Society of Hepatology
  20. ^ a b The second non-alcoholic steatohepatitis (NASH) pick-up “Fib-2 index” (PDF) Fukui Saiseikai Hospital
  21. ^ Progression of fatty liver to cirrhosis and hepatocellular carcinoma Web Medical News, Japan Medical News
  22. ^ Junji Otsuka, Yutaka Chifu,A Case of Adult Reye Syndrome "Journal of the Japanese Society of Gastroenterology" 2001 Vol. 98, No. 2, p.184-187, two:10.11405 / nisshoshi1964.98.184
  23. ^ Kimihiko Shiraishi, Hiromichi Ito, Masahiro Sawada, etc.An example of fatty liver after extensive small bowel resection "Liver" Vol. 1982, No. 23, 6, p.656-662, two:10.2957 / kanzo.23.656
  24. ^ Yuki Kimura, Hideyuki Hyogo, Tomokazu Ishihi, etc.Usefulness of glucose tolerance test in non-alcoholic fatty liver disease "Liver" 2010 Vol. 51, No. 10, p.586-588, two:10.2957 / kanzo.51.586
  25. ^ a b c d NAFLD / NASH Practice Guidelines 2014 Japanese Society of Gastroenterology
  26. ^ a b It ’s not “fatty liver” Nikkei Medical Article: June 2017, 6
  27. ^ Platelet count (Plt) BML
  28. ^ Abdominal ultrasound is now essential for all patients with lifestyle-related diseases Nikkei Medical August 2020, 8
  29. ^ Fatty liver General South Tohoku Hospital materials
  30. ^ McPherson JD, Shilton BH, Walton DJ (March 1988). “Role of fructose in glycation and cross-linking of proteins”. Biochemistry 27 (6): 1901–7. two:10.1021 / bi00406a016. PMID 3132203. 
  31. ^ Shunichi Yamauchi, "Sugars-especially fructose-“Gout and Nucleic Acid Metabolism” 2010 Volume 34 Issue 2 p.219-, two:10.6032 / gnam.34.219
  32. ^ a b Is Sugar Toxic? The New York Times, April 2011, 4
  33. ^ The Fructose Epidemic Robert H. Lustig
  34. ^ Kazuo Funatsu, Takeshi Yamashita, Yu Homma, etc.Examination of blood hemoglobin level in fatty liver"Ningen Dock," 2005, Vol. 20, No. 1, p.32-37, two:10.11320 / ningendock2005.20.32
  35. ^ Kanazawa Medical University Tell me!Doctor 10th
  36. ^ Alcoholic liver disease (See especially the "Prognosis" section)
  37. ^ a b c Akinobu Kato, Kazuyuki Suzuki, "Nutrition therapy for liver disease"Journal of the Japanese Society of Gastroenterology" 2007 Vol. 104, No. 12, p.1714-1721, two:10.11405 / nisshoshi.104.1714
  38. ^ "Inositol-acts as a vitamin-like substanceP.1
  39. ^ "Inositol-acts as a vitamin-like substanceP.2

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