antioxidants
Review

Involvement of Intracellular TAGE and the TAGE–RAGE–ROS
Axis in the Onset and Progression of NAFLD/NASH
Akiko Sakasai-Sakai *,† , Kenji Takeda

and Masayoshi Takeuchi *,†Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku,
Uchinada-machi, Ishikawa 920-0293, Japan* Correspondence: asakasai@kanazawa-med.ac.jp (A.S.-S.); takeuchi@kanazawa-med.ac.jp (M.T.)† These authors contributed equally to this work.

Abstract: The repeated excessive intake of sugar, a factor that contributes to the onset of nonalcoholic
fatty liver disease (NAFLD) and its progression to the chronic form of nonalcoholic steatohepatitis(NASH), markedly increases the hepatocyte content of glyceraldehyde (GA), a glucose/fructose
metabolic intermediate. Toxic advanced glycation end-products (toxic AGEs, TAGE) are synthesizedby cross-linking reactions between the aldehyde group of GA and the amino group of proteins, andtheir accumulation has been implicated in the development of NAFLD/NASH and hepatocellular
carcinoma (HCC). Our previous findings not only showed that hepatocyte disorders were inducedby the intracellular accumulation of TAGE, but they also indicated that extracellular leakage resulted
in elevated TAGE concentrations in circulating fluids. Interactions between extracellular TAGE andreceptor for AGEs (RAGE) affect intracellular signaling and reactive oxygen species (ROS) production,
which may, in turn, contribute to the pathological changes observed in NAFLD/NASH. RAGE plays
a role in the effects of the extracellular leakage of TAGE on the surrounding cells, which ultimately
promote the onset and progression of NAFLD/NASH. This review describes the relationships
between intracellular TAGE levels and hepatocyte and hepatic stellate cell (HSC) damage as well as
the TAGE–RAGE–ROS axis in hepatocytes, HSC, and HCC cells. The “TAGE theory” will provide
novel insights for future research on NAFLD/NASH.

Citation: Sakasai-Sakai, A.; Takeda,
K.; Takeuchi, M. Involvement of

Keywords: advanced glycation end-products (AGEs); toxic AGEs (TAGE); receptor for AGEs (RAGE);
nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH); hepatocellular
carcinoma (HCC)

Intracellular TAGE and the
TAGE–RAGE–ROS Axis in the Onset
and Progression of NAFLD/NASH.
Antioxidants 2023, 12, 748. https://doi.org/10.3390/antiox12030748
Academic Editor: Stanley Omaye
Received: 23 January 2023
Revised: 15 March 2023
Accepted: 16 March 2023
Published: 19 March 2023

Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms andconditions of the Creative Commons
Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

1. Introduction
Nonalcoholic fatty liver disease (NAFLD) covers of a broad spectrum of chronic liverdiseases (CLD) ranging from nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) to cirrhosis and/or hepatocellular carcinoma (HCC). NAFLD is a worldwide
health issue and potentially the most important CLD in the developed world in the 21st century [1]. The number of patients with NAFLD has been rapidly increasing, and is estimatedto affect between 25 and 30% of the general adult population worldwide [2,3]. Approximately 3 to 6% of NAFLD patients may also have NASH as an underlying disease [4,5].
NAFLD has also been implicated in other medical conditions, such as insulin resistance(IR), obesity, metabolic syndrome (MS), cardiovascular disease (CVD), and type 2 diabetes
mellitus (T2DM). Numerous studies, including extensive reviews, have confirmed theprogression of NALFD through the stages of steatosis, ballooning, inflammation, fibrosis,
cirrhosis, and HCC [1,6]. However, the pathogenesis of the sequential stages of NAFLD
remains unclear.
Hyperglycemia initiates and contributes to the progression of a non-enzymatic glycation reaction between proteins that results in the production of advanced glycation
end-products (AGEs), the types of which are dependent on the reducing sugars or carbonyl

Antioxidants 2023, 12, 748. https://doi.org/10.3390/antiox12030748

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compounds involved in the reaction [7,8]. AGEs formed from glyceraldehyde (GA), afructose (Fru)/glucose (Glu) metabolic intermediate, are highly cytotoxic and, thus, arecalled toxic AGEs (TAGE). Our recent findings showed that intracellular TAGE damaged
not only liver cells [9–12], but also other cell types, including neuroblasts, pancreatic cancer
cells, cardiomyocytes, myoblasts, pancreatic islet β-cells, osteoblasts, and cardiac fibroblasts [13–19]. The leakage of cytotoxic intracellular TAGE into the blood has been suggested
to increase their concentration in circulating fluids [20–22]. Extracellular TAGE and receptor
for AGEs (RAGE) interactions were found to affect intracellular signaling, gene expression,and the release of pro-inflammatory molecules and promoted reactive oxygen species (ROS)
production in many cell types [23–27], and these changes collectively contribute to thedevelopment of NASH.
Processed foods with a high content of sugar (Fru, high-Fru corn syrup (HFCS),
and sucrose), sugar-sweetened beverages (SSB) [28] and/or dietary AGEs (mainly Glu/Fru-AGEs [29]), when consumed repeatedly and at excessive amounts, have been implicated in the development of obesity and MS as well as the onset and progression of
NAFLD/NASH, T2DM, and CVD; however, the mechanisms responsible have not yet been
elucidated [30–34]. A range of “parallel hits”, such as nutritional factors, environmental
elements, IR, and oxidative stress, play a role in the progression of NAFL to NASH [35]. The
chronic excessive intake of sugars has been shown to affect hepatic metabolism, resulting
in high GA levels, which leads to the production of and increases in TAGE [20,21,27].
This review describes the relationships between the intracellular production andaccumulation of TAGE and hepatocyte damage as well as the TAGE–RAGE–ROS axis in
hepatocytes, hepatic stellate cells (HSC), and HCC cells.
2. Production of AGEs in the Human Body
Seven different classes of AGEs and Nε -(carboxymethyl)lysine (CML) have been
identified in human serum [36–39] (Figure 1). Since GA-derived AGEs are highly cytotoxic [40], we proposed the novel concept of TAGE [41]. We prepared a specific anti-TAGE
antibody that bound to epitopes to GA-derived structures, but not to AGEs with wellcharacterized CML and Nε -(carboxyethyl)lysine [37]. In addition to these structures, theanti-TAGE antibody did not recognize various AGEs produced from reducing sugars
and carbonyl molecules, such as pentosidine, pyrraline, argpyrimidine, crossline, andglyoxal (GO)-/methylglyoxal (MGO)-lysine dimers [37,42]. Although the anti-TAGE antibody did not bind to AGEs with structures that had not been elucidated, including Glu/GA-/Fru-/GO-/glycolaldehyde-/MGO-/3-deoxyglucosone-derived AGEs [37,42], itsbinding to different epitopes to GA-AGE-derived structures, such as GLAP (a 3-hydroxy-5hydroxymethyl-pyridinium compound) [43], triosidines [44], and MG-H1 (a MGO-derived
hydroimidazolone compound) [45]). None of these structures showed AGE-specific fluorescence or protein cross-linking. Two compounds with a 1,4-dihydropyrazine ring thatshowed fluorescence and had cross-links were identified as TAGE candidate structures[PCT/JP2019/34195].
We previously demonstrated that serum AGE fractions from patients with diabetic
nephropathy with hemodialysis (DN-HD) were neurotoxic and that the anti-TAGE antibody
neutralized these effects [40,46]. Therefore, among GA-derived AGE structures, only thoseto which the anti-TAGE antibody binds appear to be cytotoxic. Accordingly, AGEs thatbind the anti-TAGE antibody were referred to as toxic AGEs (TAGE) [47,48].
The amino/guanidino groups of proteins and reducing sugars (glyceraldehyde (GA),glucose, and fructose) react in a non-enzymatic manner and produce reversible Schiffbases and Amadori products/Heyns products. AGEs, heterogeneous fluorescent derivatives, are the products of the irreversible cross-linking of these early glycation products
through further rearrangements, dehydration, condensation reactions, and other complex
reactions. Glu-AGEs: glucose-derived AGEs; CML: Nε -(carboxymethyl)lysine; GA-AGEs:
glyceraldehyde-derived AGEs; TAGE: toxic AGEs; Fru-AGEs: fructose-derived AGEs; GO-Antioxidants 2023, 12, 748

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AGEs: glyoxal-derived AGEs; Glycol-AGEs: glycolaldehyde-derived AGEs; MGO-AGEs:
methylglyoxal-derived AGEs; 3-DG-AGEs: 3-deoxyglucosone-derived AGEs.

Figure 1. Numerous pathways for the in vivo generation of AGEs.

Figure 1. Numerous pathways for the in vivo generation of AGEs.

3. The Intracellular
Generationof TAGEin the Liver (GA),The amino/guanidinogroups ofproteins andand Accumulation
reducing sugars(glyceraldehyde
glucose, and fructose)react
in a non-enzymaticmannerand produce
reversible (ii)
SchiffbaCells
produceGA through threepathways[49]: (i) glycolysis,
fructolysis,
and
(iii)
the
polyolpathway,which
increases
theproduction
of
TAGE
by
intracellular
proteins.
ses and Amadori products/Heyns products. AGEs, heterogeneous fluorescent derivatives,
plays animportant roleofintheseGlu metabolism.
GA-3-Pdehydrogenase
are the products(i)ofGlycolysis
the irreversible
cross-linking
early glycation
products
through(GAPDH)
metabolizes
GA-3-phosphate(GA-3-P),anintermediateof
thispathway.
GA-3-P accufurther rearrangements, dehydration, condensation reactions, and other complex reacmulates with a decrease in GAPDH activity
and,
thus,
is
shiftedtoanother
metabolictions. Glu-AGEs: glucose-derived AGEs; CML: Nε-(carboxymethyl)lysine; GA-AGEs:
pathway for its non-enzymatic dephosphorylation to GA [50]. (ii) Fructolysis is crucial
glyceraldehyde-derived
AGEs; TAGE: toxic AGEs; Fru-AGEs: fructose-derived AGEs;
for Fru metabolism, particularly in the liver. Fructokinase rapidly phosphorylates Fru to
GO-AGEs: glyoxal-derived
AGEs;
Glycol-AGEs:
AGEs; MGOFru-1-phosphate,
whichis cleaved by glycolaldehyde-derived
aldolase B to GA and dihydroxyacetone
phosphate
AGEs: methylglyoxal-derived
AGEs;
3-DG-AGEs:
3-deoxyglucosone-derived
AGEs.
(DHAP) [51]. (iii)Underhyperglycemic
states in tissues that do notdepend directly on
insulin to absorb glucose, including the liver, brain, and heart, aldose reductase catalyzes
the conversionof andGlu tosorbitol in the ofpolyolpathway,sorbitol is then converted to3. The Intracellular
Generation
Accumulation
TAGE
in theand
Liver
FruGA
by sorbitol[50].
Fru(i)isglycolysis,
subsequently
by thefructolytic
Cells produce
throughdehydrogenase
three pathways[49]:(ii) metabolized
fructolysis, and(iii)
pathway to GA.
the polyol pathway, which increases the production of TAGE by intracellular proteins. (i)MGO is mainly produced as a byproduct of glycolysis via the non-enzymatic degradaGlycolysis playstion
an important
roleDHAP,
in Gluthe
metabolism.
dehydrogenase(GAPDH)of GA-3-P andintermediateGA-3-P
productsof glycolysis. Glycolysis
contributes
metabolizes GA-3-phosphateintermediateof thispathway.
GA-3-P
accumuapproximately (GA-3-P),
90% of the an
totalamount of MGO,withthe remaining
10%
being generated
lates with a decrease
GAPDH
activity ofand,shifted to anothermetabolicpathway
fromintheauto-oxidation
Gluthus,and isdegradationof glycatedproteins(Amadori products) [52]and dysregulatedto
lipid
associatediswith
the hepatic
for its non-enzymatic
dephosphorylation
GAmetabolism[50]. (ii) Fructolysis
crucialfor Fruaccumulation
meof triglycerides[53].Fructokinase
Previous studies
reportedelevated levels
in patientstabolism, particularlyin the liver.
rapidlyphosphorylates
FruoftoMGO-AGEs
Fru-1-phoswith
liver
disease[54].
Serum
MGO-AGEs
andsoluble
form
of
RAGE
(sRAGE)phate, which is cleaved by aldolase B to GA and dihydroxyacetone phosphate (DHAP) levels in
non-DM patients states
are associatedwiththat
NAFLD.
In depend
addition,directly
liver steatosis
and inflammation[51]. (iii) Under hyperglycemicin tissues
do noton insulintohave been shown to increase serum levels of MGO-AGEs.
absorb glucose, including the liver, brain, and heart, aldose reductase catalyzes the conversion of Glu to sorbitol in the polyol pathway, and sorbitol is then converted to Fru bysorbitol dehydrogenase [50]. Fru is subsequently metabolized by the fructolytic pathway
to GA.
MGO is mainly produced as a byproduct of glycolysis via the non-enzymatic degradation of GA-3-P and DHAP, the intermediate products of glycolysis. Glycolysis contrib-

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We recently demonstrated that the excess consumption of 10% HFCS 55 (Fru 55%/Glu
45%) increased intracellular TAGE levels in normal rat livers and serum TAGE levels [55,56].
The HFCS-induced promotion of TAGE generation in normal rat livers may increase therisk of NAFLD/NASH. Furthermore, TAGE-induced cell death may increase the cellularleakage of TAGE, which then interact with RAGE on the surrounding cells. Therefore,
intracellular TAGE may spread throughout the body.
4. The TAGE–RAGE Axis
Receptor-dependent/-independent mechanisms have been shown to play a role incellular dysfunction and tissue damage caused by AGEs. A previous study examineddifferent classes of biological reactions mediated by RAGE and identified a number ofAGE-binding proteins [48]. RAGE is a multiligand cell surface protein that functions asa pattern recognition receptor and is a member of the immunoglobulin superfamily, thecharacteristics of which have been intensively investigated [57–59]. RAGE is present within
the plasma membrane in an oligomeric or preassembled state [60–62]. The majority ofhealthy adult tissues express low levels of RAGE; however, its expression is up-regulated
under pathological conditions, such as T2DM, CVD, and cancer [23,62,63].
Previous studies reported that TAGE and RAGE interactions activated the transcription
factors NF-κB/AP-1 and Rac-1/cdc42, which, in turn, induced cellular responses throughdistinct pathways, thereby producing cytokines and triggering cell migration [59]. RAGE
is expressed by different cell types, such as hepatocytes, HSC, endothelial cells (EC), andpericytes [25]. Previous studies demonstrated the contribution of the RAGE signaling
pathway to the onset and progression of many types of liver injury [64,65]. The bindingof RAGE and TAGE was shown to induce the generation of oxidative stress followed byinflammatory responses in various cell types, including hepatocytes and HSC [64].
We previously investigated the binding affinity of AGEs to RAGE. We conductedin vitro experiments to examine the binding of the seven distinct classes of AGEs and CML,
which were identified in blood collected from DN-HD patients [36–39], to RAGE using apurified human RAGE protein, and found that the dissociation constant for TAGE was
0.36 µM. Similar binding kinetics were noted in cellular assays using COS-7, a fibroblastlike cell line expressing RAGE [66,67]. The following in vivo roles of TAGE and RAGE were
demonstrated: (i) the anti-TAGE antibody neutralized the neurotoxic effects of various AGE
structures in a serum fraction collected from DN-HD patients [40]; (ii) the neurotoxicity
of AGE-rich serum collected from DN-HD patients against EC was also exhibited by
TAGE [68].
The strong binding of TAGE to RAGE has been shown to induce a number of intracellular effects. Previous studies in many cell types reported that the TAGE–RAGE axis
promoted the production of ROS through the activation of nicotinamide adenine dinucleotide phosphate-reduced oxidase (NOX), the expression of vascular endothelial growth
factor (VEGF), and the generation of inflammatory cytokines [24,25,69,70], and thus, hasbeen implicated in not only the onset, but also the progression of NAFLD/NASH. The
TAGE–RAGE axis may also play a role in diabetic retinopathy as well as NAFLD/NASH.
AGEs have been shown to increase vascular permeability via the phosphorylation of vascular endothelial (VE)-cadherin, an adhesion complex protein in adherens junctions, following
the phosphorylation of Src, a tyrosine kinase, by ROS produced via NOX [71]. We recently
demonstrated that TAGE disrupted adherens junctions and tight junctions and increased
vascular permeability in EC [72]. Ras guanyl nucleotide-releasing protein 2 was found toprotect against the TAGE-induced disruption of VE-cadherin, suggesting its potential in
the development of novel therapies for TAGE-induced diabetic retinopathy [72].
As AGE receptors, AGE-R1 (OST-48)/-R2 (80K-H)/-R3 and the scavenger receptor
family (classes A, B, E, and H), among others, and stabilin-1/-2, which have the opposite
function to RAGE, are essential for maintaining AGE homeostasis [25,48]. Previous studies
demonstrated that the expression of AGE receptors fluctuated among different cell andtissue types as a result of metabolic changes [73,74]. However, it currently remains unclear

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whether TAGE in addition to RAGE bind to these receptors and if AGE receptors inhibit
the toxicity of TAGE.
5. Serum TAGE Levels and NASH/Non-B, Non-C (NBNC)-HCC
NAFLD covers a broad spectrum of diseases from NAFL to NASH. Since an excessive
intake of sugar is considered to be one of the factors contributing to the onset of NASH,
the relationship between TAGE and NASH has been investigated. AGEs, such as GluAGEs, CML, and TAGE, were measured in the sera of 66 patients with histologicallydefined NASH without cirrhosis, 10 with NAFL, and 30 control subjects [75]. The levelsof TAGE in the sera of NASH patients were significantly higher than those in the sera of
NAFL patients and healthy controls. Serum TAGE levels were also examined as a marker
to discriminate between NAFL and NASH. Receiver operating characteristic curves forserum TAGE showed a threshold of 8.53 U/mL for predicting NASH. At this threshold,sensitivity and specificity were 66.7 and 88.9%, respectively. Furthermore, serum TAGE
levels positively correlated with the homeostasis model assessment of IR (HOMA-IR) andinversely correlated with adiponectin levels. However, no significant differences wereobserved in Glu-AGEs or CML levels among the above groups. TAGE were also detectedin the hepatocytes of patients with NASH, but were negligible in those with NAFL. Thesefindings were not obtained using Glu-AGEs or CML [75].
Elevated TAGE levels in NASH and variations in TAGE levels with the attenuation of
NASH are important for their superiority as a biomarker. We previously reported decreases
in serum TAGE levels in 43 biopsy-proven NASH patients with dyslipidemia treatedwith the HMGA-CoA reductase inhibitor atorvastatin [76]. The activities of γ-glutamyltranspeptidase (γ-GTP) and alanine aminotransferase significantly decreased in all patientstreated for six months with atorvastatin at 10 mg/day. Furthermore, these patients had
significantly lower serum TAGE levels, with increased plasma adiponectin levels anddecreased tumor necrosis factor-α (TNF-α) levels in NASH and NAFL patients.
TAGE may also be used as a biomarker to differentiate between NBNC-HCC and
NASH. TAGE levels in the sera of NBNC-HCC patients were significantly higher than thosein the sera of NASH patients without HCC and control subjects [77]. Serum TAGE levels(inversely) independently correlated with age, γ-GTP levels, and high-density lipoproteincholesterol levels in a multiple stepwise regression analysis.
We also demonstrated that increases in the serum levels of TAGE positively correlatedwith sRAGE levels in non-DM/DM subjects, which may reflect the expression of RAGE in
tissues [78–82].
Collectively, these findings suggest the potential of serum TAGE levels as a biomarker
of NASH progression and TAGE–RAGE axis activation.
6. Cytotoxicity of TAGE in the Liver
SSB and processed foods with a high sugar content (i.e., HFCS and sucrose) [28],when consumed repeatedly and at excessive amounts, affect hepatic metabolism andpromote the production of GA, which ultimately leads to the formation of TAGE. Basedon their intracellular and extracellular cytotoxic properties, TAGE have been suggested tocontribute to not only the onset, but also the progression of NASH [9–12,25,26,69,70,83–85].
The cytotoxicity of TAGE in hepatocytes and the role of HSC in the onset and progressionof NASH are discussed below.
6.1. Intracellular TAGE and Hepatocyte Cell Death
Hepatocyte cell death is one of the hallmarks of NASH. Since a more detailed understanding of the causes of hepatocyte cell death will provide insights into the pathogenesisof NASH, the relationship between the accumulation of TAGE and cell death is being
examined. Cell death correlated with the accumulation of TAGE in HCC cell lines (HepG2and Hep3B), hepatocyte-like cells (HLC) differentiated from human induced pluripotent
stem cells (hiPSC) (hiPSC-HLC), and primary cultured hepatocytes [9–12]. Moreover,Antioxidants 2023, 12, 748

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necrosis-like cell death occurred in HepG2 cells in which TAGE had accumulated, which,in turn, appeared to elicit massive inflammatory responses in the surrounding cells [10].
Necrosis-like cell death has been shown to occur at sites of NASH disease [86], suggestingthat one of the causes of necrosis-like cell death is the accumulation of TAGE.
6.2. TAGE-Modified Proteins and Hepatocyte Cell Damage
The accumulation of TAGE in hepatocytes correlates with cell death, and functional
abnormalities as a result of TAGE modifications to various proteins may be expected in thecell death process. Proteins that are crucial for the maintenance of cellular functions are
subject to TAGE modifications.
(i) TAGE modifications and a decrease in the chaperone activity of the heat shock
cognate 70 (Hsc70) protein without changes to its mRNA expression level were detected
in GA-treated Hep3B cells [9]. Intracellular protein homeostasis is maintained by Hsc70
through its regulation of protein folding, transport, and degradation [87]. The loss ofthe chaperone activity of TAGE-modified Hsc70 indicated a lack of intracellular protein
quality control.
(ii) Previous studies demonstrated that TAGE targeted the RNA-binding protein,heterogeneous nuclear ribonucleoprotein M (hnRNPM) in Hep3B cells cultured in media
containing GA or a high Fru content [83,84]. hnRNPM is involved in a number of processes
in the metabolism of nucleic acids, such as alternative splicing, the stabilization of mRNA,and regulation of transcription and translation. Furthermore, the knockdown of hnRNPM
was found to up- or down-regulate the expression of genes associated with extracellularexosome-containing extracellular spaces [84]. Due to its potential as a biomarker of NASH,
further studies are needed on the role of hnRNPM in the extracellular space.
(iii) Caspase-3 plays an important role in apoptosis and be targeted by TAGE in
GA-treated HepG2 cells. Caspase-3 was shown to be cleaved and activated during apoptosis, resulting in protease activity [88]. However, as TAGE-modified caspase-3 levels
increased, reductions were noted in protease activity and the cleavage of poly (ADP-ribose)polymerase, which is downstream of caspase-3 in the apoptotic cascade. A previous
study reported that necrotic-like cell death was enhanced by elevations in TAGE-modified
caspase-3 levels [10]. Although the relationship between TAGE-modified caspase-3 andnecrosis-like cell death currently remains unknown, TAGE-modified caspase-3 may play animportant role in the mechanisms underlying cell death in the pathogenesis of NASH [85].
6.3. Oxidative Stress and Its Response Associated with Intracellular TAGE in Hepatocytes
Although hepatocyte cell death is a common feature of NASH, the contributing factors
and the mechanisms underlying its pathogenesis have yet to be clarified. TAGE-induced
protein dysfunction is expected to suppress stress defense mechanisms in cells, which may
easily lead to cell death. Further studies on the mechanisms responsible for TAGE-induced
cell death are needed to elucidate its relevance to NASH.
Oxidative stress is a typical factor of stress induced in cells, and its involvement in
the pathogenesis of disease has been reported in relation to NASH [89]. HepG2 cell deathcorrelated to the intracellular accumulation of TAGE was recently shown to be inhibitedby N-acetyl-L-cysteine, an antioxidant [11]. Furthermore, increases in ROS levels wereobserved in GA-treated HepG2 cells and human primary hepatocytes, suggesting the
involvement of accumulated TAGE in intracellular oxidative stress and ROS-induced cell
death [11].
Intracellular oxidative stress may be attributed to the collapse of oxidative defense
mechanisms or an increase in ROS generation. Antioxidant defense mechanisms in cells
include the transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2), which
activates a number of detoxification enzymes [90]. Nrf2 plays an important role in NAFLD
and NASH. A previous study demonstrated that the onset and progression of NASH
were rapid in mice with a Nrf2 deficiency [91]. Furthermore, NASH patients with lower
glutathione levels exhibited the higher expression of hemeoxygenase-1 (HO-1), which

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are downstream of Nrf2 [92]. In addition, catalase activity was increased in the livers ofmice fed a high-Fru plus high-fat diet, which was expected to result in the accumulationof TAGE, and these mice also showed fat accumulation and increased inflammation [93].
Furthermore, the expression of Nrf2 and HO-1 was up-regulated and catalase activity wasmaintained in GA-treated HepG2 cells [11]. On the other hand, mitochondrial abnormalities
have been shown to enhance intracellular oxidative stress under conditions of increased
ROS generation [89]. An increase in ROS correlated with mitochondrial abnormalities in
HepG2 cells treated with GA [11]. The multiple parallel hits theory has been proposed
as a cause of NASH progression. In the case of TAGE accumulation, which has beensuggested as one of the causes of NASH progression, the main phenotype is predicted to be
an increase in oxidative stress due to mitochondrial abnormalities that cause cytotoxicity,rather than a reduction in antioxidant function as the pathogenic pathway.
A relationship has been reported between the production of ROS and inflammation. A
previous study demonstrated that ROS up-regulated the expression of C-reactive protein(CRP) in the human normal liver cell line, L-02 [94]. Furthermore, the intracellular accumulation of TAGE in Hep3B cells was associated with the up-regulated expression of CRP
mRNA [9]. Inflammatory responses associated with TAGE accumulation have been detected not only in HCC cells, but also in hiPSC-HLC [12]. Furthermore, the accumulation of
TAGE in hiPSC-HLC correlated with the up-regulated expression of inflammation-related
genes, including monocyte chemoattractant protein-1 (MCP-1) and interleukins 6 and8 [12]. Experimental data from hiPSC-HLC as a model of human liver cells derived from
non-cancer cells more accurately reflect the disease pathology of humans. The correlation
between TAGE accumulation and inflammation in the HCC cell lines HepG2/Hep3B andhiPSC-HLC implicates TAGE accumulation in the liver as a cause of inflammatory NASH.
Collectively, these findings indicate that increases in intracellular ROS production
with the accumulation of TAGE cause inflammation and, ultimately, cell death, and provide
novel insights into the contribution of TAGE to the onset and progression of NASH.
6.4. Effects of Extracellular TAGE on Hepatocytes
Extracellular TAGE are also involved in inflammatory responses in hepatocytes. The
TAGE–RAGE axis promotes inflammation in hepatocytes. A previous study reported
increases in the expression levels of CRP in TAGE-treated Hep3B cells [70]. Furthermore,
Rac-1 mediated the expression of CRP by activating NF-κB or NOX [95], the expressionof which was high in NASH patients/mice [96,97]. NOX is expected to generate ROS andenhance inflammation in Hep3B cells.
TAGE–RAGE signaling in Hep3B cells has been detected in EC. EC dysfunction has
been implicated in the progression of NAFLD [98]. NOX-induced ROS generation via
the TAGE–RAGE axis was previously shown to be mediated by the activation of the transcriptional factors NF-κB and AP-1 [68,99,100]. The TAGE–RAGE axis was also activatedby inflammatory and thrombogenic reactions in EC via the expression of plasminogenactivator inhibitor-1, intercellular adhesion molecule-1 (ICAM-1), and MCP-1 through the
production of ROS [24,101–103].
These findings suggest that TAGE induces inflammation through its extracellularand intracellular effects and contributes not only to the onset, but also the progression of
NAFLD/NASH.
6.5. Effects of Extracellular TAGE on HSC
In CLD, including NASH, the pathological accumulation of extracellular matrix (ECM)
proteins leads to liver fibrosis, the progression of which induces cirrhosis [104]. In CLD,
HSC are activated by various cytokines, including transforming growth factor-β1 (TGF-β1),
platelet-derived growth factors, and TNF-α, and differentiate into myofibroblast-like cells,
which then secrete high levels of ECM material, such as collagen type I (COL-I) [105].
Intracellular oxidative stress was previously induced in TAGE-treated LI90 cells, ahuman HSC line, through the production of RAGE-NOX-derived ROS [106]. Furthermore,Antioxidants 2023, 12, 748

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the up-regulated expression of the genes and proteins that play roles in fibroblastogenesis
and inflammation, including α-smooth muscle actin, COL-Iα2, TGF-β1, and MCP-1, wasobserved in these cells. Therefore, TAGE appear to be involved in the onset and progressionof liver fibrosis by promoting ROS production and HSC activation via RAGE.
TGF-β1-induced apoptosis in the human HSC line LX-2 was inhibited by TAGE. In
addition, the culture medium of LX-2 cells co-treated with TGF-β1 and TAGE showedsignificantly elevated levels of the COL-I protein, whereas COL-I expression levels remained unchanged [107]. Based on these findings, TAGE promoted the generation of ECM
molecules, such as COL-I, through the suppression of apoptosis in TGF-β1-activated HSC.
These findings suggest that TAGE worsens liver fibrosis in chronic hepatitis patients,
such as those with NASH.
6.6. Extracellular TAGE and the Malignant Progression of NASH-Related HCC
The progression of NASH is associated with an increased risk of the onset of cirrhosisand HCC. The TAGE–RAGE axis has been suggested to play a role in the malignant
progression of NASH-related HCC. Elevated CRP levels predict a poor clinical outcome
in HCC patients. TAGE were previously found to increase CRP expression levels in HCC,
and this was prevented by a pretreatment with anti-RAGE antiserum. Moreover, the risk ofthe malignant transformation of HCC was reduced by sRAGE, a decoy receptor of RAGE.
These findings indicate the potential of the TAGE–RAGE axis as a therapeutic target for
NASH-related HCC [70].
In addition to CRP, VEGF expression levels were previously shown to be elevated in
HCC [108]. TAGE up-regulated the expression of VEGF in Hep3B cells [69]. Furthermore,
proteins secreted by TAGE-treated Hep3B cells promoted the angiogenesis of EC, which isimportant for tumorigenesis, indicating that the TAGE–RAGE signaling pathway increased
the angiogenic potential of HCC cells by up-regulating the expression of VEGF [69]. A
relationship has been reported between TAGE and VEGF not only in hepatocytes, but also
in vivo. A high-AGE beverage orally administered to rats induced the hepatic expressionof VEGF and accumulation of Glu-AGEs, which predicted increases in TAGE due toabnormalities in the intracellular metabolism of Glu [24,109]. These findings suggest that
dietary AGEs play a pathological role in the progression of HCC.
We previously demonstrated that the expression of VEGF was up-regulated by NOXinduced ROS production via the TAGE–RAGE axis through the transcriptional activationof NF-κB and AP-1, which, in turn, increased the proliferation of EC and tube formation,
key factors in tumor angiogenesis [69,99,110,111]. Furthermore, inflammatory and thrombogenic reactions were induced in EC by the activation of the TAGE–RAGE axis throughthe up-regulated expression of MCP-1 and ICAM-1 via ROS [101–103,112].
Therefore, TAGE appear to play a role in the proliferation and invasion of cancer cells
through RAGE interactions.
6.7. Limitations
TAGE stress in NASH is being investigated both in vivo and in vitro, including clinicalspecimens, animal models, and cells. Insights have been obtained into the relationshipbetween TAGE stress and oxidative stress, particularly from studies using hepatocytes, andfurther research on TAGE target molecules is expected in the future. AGEs and ROS areclosely related, and relationships have been reported for other AGEs and diseases [113,114].
While the findings obtained on other AGEs are important, this review focused on TAGE,
which is relevant to NASH.
The majority of studies conducted on AGEs to date have examined the effects of theAGE-RAGE axis from outside of the cell, and thus, a more detailed understanding of thecytotoxic effects of intracellular AGEs is important. Further studies on the effects of TAGE
produced by Glu/Fru metabolism are needed.

Antioxidants 2023, 12, 748

on TAGE, which is relevant to NASH.
The majority of studies conducted on AGEs to date have examined the eﬀects of theAGE-RAGE axis from outside of the cell, and thus, a more detailed understanding of thecytotoxic eﬀects of intracellular AGEs is important. Further studies on the eﬀects of TAGE
produced by Glu/Fru metabolism are needed.
9 of 16
7. Conclusions and Perspectives
SSB and/or processed foods in the modern daily diet, when consumed repeatedly
7. Conclusions and Perspectives
and at excessive amounts, elevate cellular levels of GA and promote TAGE modifications
SSB and/or
processedin the modern
daily diet, when
repeatedlywith
andto intracellular
proteins.
Thefoods
accumulationof intracellular
TAGEconsumed
has been associatedatexcessive
amounts,
elevatecellularlevelsofGAandpromoteTAGE
modifications
tocell death, which may contribute to the leakage of TAGE into extracellular regions andintracellular proteins. The accumulation of intracellular TAGE has been associated withincreases in serum TAGE levels. Extracellular TAGE contribute to not only the onset, but
cell death, which may contribute to the leakage of TAGE into extracellular regions andalso the progression of NAFLD/NASH through their activation of the TAGE–RAGE axis,
increases in serum TAGE levels. Extracellular TAGE contribute to not only the onset, butwhich enhances ROS generation and increases RAGE expression levels (Figure 2). The
also the progression of NAFLD/NASH through their activation of the TAGE–RAGE axis,“TAGE theory” provides novel insights for future studies on NAFLD/NASH and HCC.
which enhances ROS generation and increases RAGE expression levels (Figure 2). The“TAGE theory” provides novel insights for future studies on NAFLD/NASH and HCC.

Figure 2. Involvement of intracellular TAGE and the TAGE–RAGE–ROS axis in the onset andprogression of NAFLD/NASH.

The chronic intake of excessive amounts of SSB and processed foods increases cellularlevels of the sugar metabolite GA, which, in turn, enhances TAGE production. TAGE
accumulation is associated with the loss of protein function and mitochondrial membraneabnormalities. Damage to mitochondria results in the intracellular production of ROS,
which ultimately leads to hepatocyte death. TAGE-modified proteins that accumulate
intracellularly are expected to leak out of cells upon cell death and exert various effects
on the surrounding cells via the TAGE–RAGE axis. The TAGE–RAGE axis promotes the
production of ROS by NOX. TAGE-induced ROS production may be one cause of oxidative
stress in NASH. Redox-sensitive transcription factors, including NF-κB, may be activated
by ROS, which, in turn, promotes the production of cytotoxic, pro-inflammatory, andfibrogenic mediators by hepatocytes and/or HSC, thereby contributing to the progression

Antioxidants 2023, 12, 748

10 of 16of NAFLD/NASH. TAGE also suppress TGF-β1-induced HSC cell death and maintain
HSC. Therefore, the increased production of ECM molecules and eventual fibrosis are
expected. The interaction between TAGE and RAGE affects intracellular signaling in tumor
cells and HSC, and induces angiogenesis, invasion, migration, proliferation, and fibrosis.
This cooperation by the TAGE–RAGE axis may lead to the malignant progression of
NASH-related HCC. SSB: sugar-sweetened beverages; HFCS: high-fructose corn syrup; GA:
glyceraldehyde; TAGE: toxic AGEs; RAGE: receptor for AGEs; NOX: nicotinamide adenine
dinucleotide phosphate reduced oxidase; ROS: reactive oxygen species; Hsc70: heat shock
cognate 70; hnRNPM: heterogenous nuclear ribonucleoprotein M; NF-κB: nuclear factor
kappa B; VEGF: vascular endothelial growth factor; CRP: C-reactive protein; HSC: hepatic
stellate cells; TGF-β1: transforming growth factor-β1; MCP-1: monocyte chemoattractant
protein-1; COL-I: collagen-type I; α-SMA: α-smooth muscle actin; HCC: hepatocellular
carcinoma; EC: endothelial cell.
Author Contributions: All of the authors contributed substantially to the preparation of this review(Conceptualization, M.T.: designed the review, M.T. and A.S.-S.; original and revised draft preparation,and editing, A.S.-S. and M.T.; visualization and review, K.T.). All authors have read and agreed to the
published version of the manuscript.
Funding: This work was supported by JSPS KAKENHI Grant Numbers 21K11583 (A.S.-S.) and21H04865 (M.T.); by the Hokkoku Foundation for Cancer Research (A.S.-S.).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare that no conflicts of interest exist.

Abbreviations
The following abbreviations are used in this manuscript:
AGEs
CLD
CML
COL-I
CRP
CVD
3-DG-AGEs
DHAP
DN-HD
EC
ECM
Fru
Fru-AGEsGA
GA-AGEs
GA-3-P
GAPDH
GLAP
Glu
Glu-AGEs
Glycol-AGEs
GO
GO-AGEs
γ-GTP
HCC
HFCS

Advanced glycation end-products
Chronic liver diseaseNε -(Carboxymethyl)lysine
Collagen type I
C-Reactive protein
Cardiovascular disease
3-Deoxyglucosone-derived AGEs
Dihydroxyacetone phosphate
Diabetic nephropathy with hemodialysis
Endothelial cells
Extracellular matrix
Fructose
Fructose-derived AGEs
Glyceraldehyde
Glyceraldehyde-derived AGEs
Glyceraldehyde-3-phosphate
Glyceraldehyde-3-phosphate dehydrogenase
3-Hydroxy-5-hydroxymethyl-pyridinium compound
GlucoseGlucose-derived AGEs
Glycolaldehyde-derived AGEs
GlyoxalGlyoxal-derived AGEs
γ-Glutamyl transpeptidase
Hepatocellular carcinoma
High-fructose corn syrup

Antioxidants 2023, 12, 748

11 of 16

hiPSC
hiPSC-HLC
HLC
hnRNPM
HO-1
HOMA-IR
Hsc70
HSC
ICAM-1
IL
IR
MCP-1
MG-H1
MGO
MGO-AGEs
MS
NAFL
NAFLD
NASH
NBNC-HCC
NF-κB
NOX
Nrf2
RAGE
sRAGE
RasGRP2
ROS
α-SMA
SSB
TAGE
T2DM
TGF-β1
TNF-α
VE
VEGF

Human induced pluripotent stem cells
HLC differentiated from hiPSC
Hepatocyte-like cells
Heterogeneous nuclear ribonucleoprotein M
Hemeoxygenase-1
Homeostasis model assessment of IR
Heat shock cognate 70
Hepatic stellate cells
Intercellular adhesion molecule-1
Interleukin
Insulin resistance
Monocyte chemoattractant protein-1
Methylglyoxal-derived hydroimidazolone compound
Methylglyoxal
Methylglyoxal-derived AGEs
Metabolic syndrome
Nonalcoholic fatty liver
Nonalcoholic fatty liver disease
Nonalcoholic steatohepatitis
Non-B, non-C HCC
Nuclear factor kappa B
Nicotinamide adenine dinucleotide phosphate-reduced oxidase
Nuclear factor erythroid 2-related factor 2
Receptor for AGEs
Soluble form of RAGE
Ras guanyl nucleotide releasing protein 2
Reactive oxygen species
α-smooth muscle actin
Sugar-sweetened beverages
Toxic AGEs
Type 2 diabetes mellitus
Transforming growth factor-β1Tumor necrosis factor-α
Vascular endothelial
Vascular endothelial growth factor

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