Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : October 10, 2018
Accepted : November 11, 2018
Published online : December 31, 2018
doi:10.24659/gsr.5.4_177

Review article

Glycative stress and anti-aging: 10. Glycative stress and liver disease.
Masayuki Yagi, Yoshikazu Yonei
Anti-Aging Medical Research Center and Glycative Stress Research Center, Faculty of Life and Medical Sciences,
Doshisha University, Kyoto, Japan

Abstract

The liver is a vital organ which has a basal metabolic rate of 25%. Liver diseases include hepatitis, cirrhosis andfatty liver disease. Causes of fatty liver disease are obesity, excessive energy consumption, such as through alcohol andcarbohydrates, diabetes, and lack of exercise. Chronic and excessive alcohol consumption in patients with a fatty liver induces
alcoholic liver disease (ALD) at a ratio of 10-20%. Contrarily, fatty liver disease includes pathological conditions designatedas nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). NASH occurs in those with abackground of fatty liver due to overeating, lack of physical activity, obesity, diabetes, and even lipid abnormalities all withouta drinking history. Leaving fatty liver disease untreated is a risk factor which may lead to cirrhosis or hepatoma. Among thevarious types of AGEs (advanced glycation end products) formed in vivo, glyceraldehyde-derived AGEs (Glycer-AGEs) andacetaldehyde-derived AGEs (AA-AGEs) are involved in liver diseases. There is a possibility that Glycer-AGEs and AA-AGEs
induce protein dysfunction and influence nerve cells or liver cells, which are involved in the onset and progression of alcoholicliver disease (ALD). Moreover, varied AGEs, mainly glucose-derived AGEs (Glc-AGEs), are produced in food during heatingor processing. Intake of food containing high levels of GLc-AGEs may induce the accumulation of Glc-AGEs and GlycerAGEs in the liver. Therefore, food-derived AGEs and postprandial hyperglycemia may increase levels of Glycer -AGEs, andinduce liver diseases.

KEY WORDS: alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD),				

nonalcoholic steatohepatitis (NASH), glyceraldehyde-derived AGEs (Glycer-AGEs),
acetaldehyde-derived AGEs (AA-AGEs)

1. Introduction: liver diseases

The liver, which is a vital organ with a basal metabolic
rate of 25%, metabolizes carbohydrates, lipids, protein andvitamins, detoxifies substances and secretes bile. Furthermore,
the liver has a high regenerative capacity and thus, is aregeneratable organ, even if liver cells are destroyed. Liverdiseases include hepatitis, cirrhosis and fatty liver disease. As
patients with liver diseases rarely have subjective symptoms,
the liver is called a silent organ.
Hepatitis is classified, according to clinical conditions;mainly into acute hepatitis and chronic hepatitis(inflammation lasts for six months or longer). Based on thecauses, hepatitis is categorized into viral (A, B, C and others),
alcoholic, drug-induced, autoimmune hepatitis and others 1).

Hepatitis A is an infectious disease affecting the digestiveorgans, which is caused by the hepatitis A virus (HAV).
Consumption of virus contaminated shellfish is a major
cause of hepatitis A, which is commonly seen in regionswith unsanitary living conditions. Infection of children
mostly results in inapparent infection, while infection ofadults frequently induces an onset of hepatitis A. Hepatitis B,
which is caused by the hepatitis B virus (HBV), is classified
into transitory and persistent disease. In most cases of thepersistent type of hepatitis, the virus is passed from motherto infant. Acute hepatitis occurs rather than chronic hepatitis.
Hepatitis C, which is caused by the hepatitis C virus (HCV),
occurs regardless of season, age or sex. Hepatitis C accounts
for the majority of blood-transfusion-induced hepatitis cases,and has a high probability to become chronic.

Contact Address: Professor Masayuki Yagi, PhD
Glycative Stress Research Center,
Faculty of Life and Medical Sciences, Doshisha University
1- 3 Tatara Miyakodani, Kyotanabe, Kyoto, 610-0394 Japan

Phone/Fax: +81-774-65-6394 E-mail: myagi@mail.doshisha.ac. jp
Co-author: Yonei Y, yyonei@mail.doshisha.ac.jp_ 17 7 _Glycative Stress Research 2018; 5 (4): 177-180(c) Society for Glycative Stress ResearchGlycative Stress and Liver disease

Until recently, causes of hepatoma, which is one of
the liver diseases, was mostly through viral liver diseases,
such as hepatitis C. However, the number of nonalcoholic
cases has been increasing as a cause of hepatoma, where afatty liver is considered as a cause in many cases. A fatty
liver is induced by obesity, excessive energy consumption,such as alcohol and carbohydrates, diabetes and lack ofphysical activity. Consumption of excessive alcohol as muchas intaking five go (900 mL) of Japanese sake per day forseven consecutive days can lead to the onset of a fatty liver,even in a healthy person 2-4). Chronic and excessive alcohol
consumption of people with alcoholic fatty liver diseasecauses the onset of alcoholic liver disease (ALD) at a ratioof 10-20 %. The spectrum of liver disease is the following:
ADL develops into alcoholic fatty liver, alcoholic hepatitis
and alcohol-related cirrhosis.
Contrarily, fatty liver diseases include nonalcoholic
clinical conditions designated as nonalcoholic fatty liverdisease (NAFLD) and nonalcoholic steatohepatitis (NASH).
NASH occurs in those with a background of fatty liver due toovereating, lack of exercise, obesity, diabetes, and even lipid
abnormalities all without a drinking history. Leaving NFLD
without any treatments or interventions for five-ten years has
a 5-20 % chance to lead to the development of cirrhosis or
hepatic cancer in patients with NFLD. NASH and ALD showresemblances in histological images of liver.

2. Liver diseases and AGEs

Among diversified types of AGEs (advanced glycation
end products) formed in vivo, glyceraldehyde-derived AGEs
(Glycer-AGEs) and acetaldehyde-derived AGEs (AA-AGEs)
are involved in liver diseases 5).
It has long been recognized that AGEs are formed in vivo
mainly from glucose and protein. However, it has also
been confirmed that AGEs are formed from the metabolic
intermediates and degradation products of glucose,the intermediates of glycation, and fructose ( Fig. 1 ) 6, 7).
Furthermore, intermediates of glycation and aldehydederived AGEs form AGEs at a faster rate in comparison
to glucose-derived AGEs (Glc-AGEs) and fructosederived AGEs (Fru-AGEs). For example, in the glycation
with protein of bovine serum albumin (BSA), the speedof AGE formation is the fastest in Glycer-AGEs, followed
by glycolaldehyde-der ived AGEs (Glycol - AGEs),
methylglyoxal-derived AGEs (MGO-AGEs), glyoxal-derived
AGEs ( GO -AGEs), 3 - deoxyglucosone-derived AGEs
(3-DG-AGEs), Fru-AGEs and Glc-AGEs (Glycer-AGEs,
Glycol-AGEs > MGO-AGEs, GO-AGEs >> 3-DG-AGEs>>> Fru-AGEs > Glc-AGEs).
Particularly, Glycer-AGEs are strongly involved, via
receptor for AGEs (RAGE), in the onset and progression ofdiabetic vascular complications 7, 8). When Glycer-AGEs areFig. 1. Alternative routes for the formation of AGEs in vivo.

Glc-AGEs, glucose-derived AGEs; Glycer-AGEs, glyceraldehyde-derived, AGEs; Glycol-AGEs, glycolaldehyde-derived AGEs; MGOAGEs, methylglyoxal (MGO)-derived AGEs; GO-AGEs, glyoxal (GO)-derived AGEs; 3-DG-AGEs, 3-deoxyglucosone (3-DG)-derivedAGEs; CML, N-(carboxymethyl)lysine; P-NH2, free amino residue of protein. GOLD, GO-lysine dimmer; GA-pyridine, 3-hydroxy-4hydroxymethyl-1-(5-carboxypentyl) pyridinium cation; DOLD, 3-DG-lysine dimmer; CEL, N-(carboxyethyl)lysine; MOLD, MGO-lysine
dimmer; GLAP, glyceraldehyde derived pyridinium compound. The figure is adapted from Reference 7.

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added to a hepatocyte culture system, there is an increasein an inflammatory marker known as the C-reactive protein(CRP). Furthermore, added into the culture system ofhepatic stellate cell, which is associated with liver fibrosis,
Glycer-AGEs induce glycative stress via RAGE and elicit
inflammation 9). Glycer-AGEs are accumulated in patientswith NASH, which do not have impaired glucose tolerance 10).
When glyceraldehyde is added into the cell culture systemof Hep3B, derived from a hepatic cancer cell in humans,
apoptosis is induced in hepatocyte cells along with anincrease in the amount of Glycer-AGEs. Furthermore,
the activity of heat shock cognate 70 (Hsc70), which
is a molecular chaperon, is lowered, when modified byglyceraldehyde to Glycer-AGEs. Subsequently, throughprotein dysfunction, hepatocellular injury may develop 11).
Contrarily, acetaldehyde, which is a metabolite ofalcohol, is bound with protein to form AA-AGEs (Fig. 2 ).
AA-AGEs have strong effects on hepatocellular injury.
AA-AGEs are formed mainly in hepatic cells aroundcentral venules (Zone 3) and are involved in the onset andprogression of ALD 12). AA-AGEs are distributed in theblood or in the brain of alcohol-dependent patients 13). It has
been reported that AA-AGEs were formed mainly in hepaticcells around central venules in a chronic alcohol-treated rat
model. Judging from these reports, even after acetaldehyde
is metabolized and disappears from the blood, AA-AGEs
may be involved in the onset and progression of alcoholic
hepatopathy, affecting nerve cells or liver cells with toxicity.

3. Influences of food-derived AGEs
on the liver

Varied AGEs are produced in food during heating orprocessing. Commercial food tends to contain AGEs, mainly
Glc-AGEs or Fru-AGEs. An examination in influencesof Glycer-AGEs on a RAGE expression system, wherebeverages containing high levels of GLc-AGEs were orally
supplied to normal rats, demonstrated that the expression ofvascular endothelial growth factor (VGEF) gene increased,and Glc-AGEs and Glycer-AGE accumulated 14).
An experimental system offering a limited food supply
to type 2 diabetes model rats, confirmed that Glycer -AGEs
were formed due to postprandial blood glucose elevation 15).
In the case of the administration of α-glucosidase inhibitor topatients with type 2 diabetes, in-blood levels of Glycer-AGEs
were significantly reduced in comparison to the levels before
administration 16). Moreover, according to a survey of patientswith NAFLD, the dietary intake of sweet beverages was fivetimes higher in patients with NAFLD than in healthy people.
Excessive consumption of sugar or high fructose corn syrup
containing 55% fructose, which is added to beverages as asweetener, is associated with the onset and progression ofNAFLD 17). Judging from these, there are possibilities thatfood-derived AGEs and postprandial hyperglycemia could
increase levels of Glycer -AGEs, augment the interactionof the RAGE expression system due to Glycer -AGEs, andinduce liver diseases 18).

Acknowledgement

This work was partially supported by the JapaneseCouncil for Science, Technology and Innovation, SIP (ProjectID 14533567), “Technologies for creating next-generation
agriculture, forestry and fisheries” (funding agency: Biooriented Technology Research Advancement Institution,NARO).

Conflict of Interest Statement

The authors claim no conflict of interest in this study.

Fig. 2. Schematic representation of the formation of AA-AGE from acetaldehyde, production of ROS,and pathogenesis of ALD.

AA-AGE, acetaldehyde-derived AGE; NEL, N-ethyllysine; NADPH, nicotinamide adenine dinucleotide phosphate;
ROS, reactive oxygen species; ALD, alcoholic liver disease. The figure is adapted and modified from Reference 13.

_ 179 _Glycative Stress and Liver disease

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