Open access peer-reviewed chapter

Impact of Glyoxalase-I (Glo-I) and Advanced Glycation End Products (AGEs) in Chronic Liver Disease

Written By

Marcus Hollenbach

Submitted: January 11th, 2017 Reviewed: March 9th, 2017 Published: July 5th, 2017

DOI: 10.5772/intechopen.68417

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Abstract

Inflammation caused by oxidative stress (ROS) is a main driver for development of chronic inflammatory liver disease leading to fibrosis and cirrhosis. An important source of ROS constitutes methylglyoxal (MGO). MGO is formed as a by-product in glycolysis, threonine catabolism, and ketone bodies pathway leading to formation of advanced glycation end products (AGEs). AGEs bind to their receptor for AGEs (RAGE) and activate intracellular transcription factors, such as nuclear factor-κB (NF-κB), resulting in production of pro-inflammatory cytokines and ROS. The enzymes glyoxalase-I (Glo-I) and glyoxalase-II (Glo-II) form the glyoxalase system and are essential for the detoxification of methylglyoxal (MGO). This chapter highlights Glo-I and (R)AGE in chronic liver disease with focus on fibrosis and cirrhosis. AGEs and RAGE have been shown to be upregulated in fibrosis, and silencing of RAGE reduced the latter. In contrast, recent study highlighted reduced expression of Glo-I in cirrhosis with consecutive elevation of MGO and oxidative stress. Interestingly, modulation of Glo-I activity by ethyl pyruvate resulted in reduced activation of hepatic stellate cells and reduced fibrosis in CCl4 model of cirrhosis. In conclusion, Glo-I and R(AGE) are important components in development and progression of chronic liver disease and constitute interesting therapeutic target.

Keywords

  • ethyl pyruvate cirrhosis
  • fibrosis
  • methylglyoxal
  • AGEs

1. Introduction

Oxidate stress (reactive oxygen species, ROS) with consecutive and repetitive inflammation is responsible for development of chronic liver disease. Different etiologies of liver disease lead to damage of hepatocytes, release of pro-inflammatory cytokines, and finally activation of hepatic stellate cells (HSC). Activated HSC transform to myofibroblasts and lead to deposition of collagen, which in turn result in fibrosis and finally cirrhosis. Several molecular mechanisms are involved in this complex interplay, nevertheless the critical step is the activation of HSC by ROS. This chapter focuses on the glyoxalase-I (Glo-I) and related advanced glycation end products (AGEs) with their receptor for AGEs (RAGE) playing an important role in generation and detoxification of ROS. Current knowledge of Glo-I and (R)AGE in chronic liver disease with key aspect to fibrosis and cirrhosis will be highlighted.

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2. Pathogenesis of fibrosis and cirrhosis

End-stage liver diseases are mainly caused by viral hepatitis, alcoholism, nonalcoholic fatty liver disease or steatohepatitis (NAFLD/NASH), or rare autoimmune and hereditary disorders. The followed repetitive liver injury caused inflammation, finally resulting in fibrosis and irreversible cirrhosis. Thereby, liver cirrhosis belongs to the global burden of disease responsible for more than one million deaths p.a. [1]. In cirrhosis, altered liver anatomy and reduced liver function are pathognomonic. Development of cirrhosis is characterized by the appearance of regenerative nodules, hepatocyte ballooning, accumulation of fibrotic tissue, disturbed microcirculation, angiogenesis and sinusoidal collapse with defenestration and development of a basement membrane [2]. These alterations of liver architecture lead to reduced liver function and elevation of intrahepatic resistance demonstrated by increased portal pressure with development of ascites and esophageal varices [3, 4]. Nevertheless, portal hypertension is being caused by both structural alterations of liver microarchitecture and hepatic endothelial dysfunction. The latter is characterized by an imbalance of vasoactive components. In fact, there is an hyperresponsiveness and overproduction of vasoconstrictors (mainly endothelin-1 (ET-1)) and an hyporesponsiveness and reduction of vasodilators (mainly nitric oxide (NO)) in the vascular bed of the liver [57]. Despite this hypoactive endothelium in hepatic microcirculation, portal hypertension leads to arterial vasodilation, formation of collateral vessels, and hyporesponsiveness to vasoconstrictors due to hyperactive endothelium in splanchnic and systemic circulation with increased NO production. Finally, these alterations result in elevated blood flow to portal vein and a vicious circle of disease [811].

The underlying molecular mechanism for development of fibrosis, cirrhosis, and portal hypertension has been intensively investigated over the last decades. Since the liver is formed by parenchymal cells (mainly hepatocytes (HEP)) and nonparenchymal cells (Kupffer cells (KC), hepatic stellate cells (HSC), and liver sinusoidal endothelial cells (LSEC)), both are involved in the development of fibrosis and cirrhosis. Nevertheless, HSC are the main cell type responsible for accumulation of fibrosis and increased intrahepatic vascular resistance. HSC are pericytes surrounding the sinusoids in the space of Disse. HSC are quiescent but became activated upon various stimuli and transform to myofibroblasts [12]. This activation process is a complex interplay between parenchymal and nonparenchymal cells and triggered via inflammatory processes [13]. For instance, deleterious agents (alcohol, LPS) have direct hepatotoxic effects to hepatocytes and trigger the production of reactive oxygen species (ROS). The release of ROS, DNA, and damage-associated molecular pattern (DAMP) leading to activation of KC and innate immune system followed by subsequent production of pro-inflammatory cytokines such as TNF-α and IL-6 as well as pro-fibrotic factors [1416]. Also, alcohol consumption increases permeability of the gut resulting in increased levels of portal endotoxins (LPS) with consecutive activation of KC resulting in liver injury and inflammation [17, 18]. Furthermore, inflammation triggers the classical complement pathway activation via C1q [19], followed by production of pro-inflammatory cytokines, and inhibits components of innate immune system. As a consequence of these induced inflammatory processes, activated KC stimulate HSC subsequently leading to fibrosis [20]. This stimulation can result directly by the deleterious agent [21] or via transforming growth factor beta (TGF-β)-dependent mechanisms [22] leading to secretion of TNF-α, IL-6, TIMP-1, MCP-1, collagen-I, and α-SMA [2325] and finally collagen deposition.

As mentioned above, pro-inflammatory factors (TNF-α, IL-1β, IL-6) are also involved in the activation of HSC. In this regard, activation of the transcription factor nuclear factor-κB (NF-κB) and subsequent overexpression of pro-inflammatory cytokines are important pathways. NF-κB, thereby, is activated by growth factors, cytokines, bacterial and viral factors, and ROS and regulates by itself pro-inflammatory cytokines (like COX-2 or IL-6) [26, 27].

Beside the production of collagen and accumulation of fibrotic tissue, HSC are involved in increased intrahepatic vascular resistance not only via structural changes. Transformation of HSC to myofibroblasts was accompanied by stimulation of rho kinase leading to activation of contractile filaments of HSC and subsequently vasoconstriction of sinusoids [28].

Another key player in the development of fibrosis comprises LSEC. They form the first line of defense protecting the liver from injury. Inflammation by LPS or ROS resulted in dysfunction of LSEC [29] indicated by disturbed sinusoidal microcirculation, defenestration, hypoxia, and pathological angiogenesis [30]. In contrast, both direct deterioration of LSEC and vasoconstriction of HSC result in impaired release of vasodilators from LSEC leading to a vicious circle of disease. In this regard, disturbed regulation of NO production in cirrhosis depends on activity of endothelial NO synthase (eNOS) and increased degradation due to phosphodiesterases, that is, PDE-5 [31]. Although eNOS expression is upregulated in sinusoidal area in cirrhosis, eNOS activity has been shown to be reduced by caveolin-eNOS binding [32] and was diminished by several post-translational modifications of the endothelial NO synthase (eNOS) [9]. In contrast, in splanchnic circulation, eNOS is upregulated [9] with increased enzyme activity in portal hypertension and regulated by phosphorylation of protein kinase B (Akt) [33]. Beside upregulation of eNOS, production of NO is also related to induction of the inducible form of the NO synthase, iNOS. iNOS is mainly stimulated by the presence of endotoxin and pro-inflammatory cytokines, all of whom occur in development of cirrhosis [34]. Indeed, recent study showed stimulation of iNOS rather than eNOS in splanchnic circulation by LPS, indicating an important role of iNOS in portal hypertension after bacterial translocation to mesenteric vessels [35]. Finally, all these alterations result in a hyperdynamic circulation with elevated blood flow to portal vein and further increase of portal pressure [810].

In conclusion, cirrhosis demonstrates the end stage of liver disease with disturbed liver architecture and impaired liver function. Generation of ROS and stimulation of various inflammatory pathways are critical steps in activation of HSC as the main driver for fibrosis. Despite these findings, the use of antioxidants (vitamin E, N-acetylcysteine, coenzyme Q, and others) in patients with alcoholic liver disease has failed to show an efficacy in improving disease conditions [3638].

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3. Glyoxalase system and R(AGE)

An important role in regulation and formation of ROS and oxidative stress comprises the glyoxalase system. This enzymatic system was first discovered in 1913 [39] and constitutes two cytosolic enzymes, glyoxalase-I (Glo-I, EC 4.4.1.5) and glyoxalase-II (Glo-II, EC 3.1.2.6.). Glo-I is responsible for the catalytic conversion of α-oxo aldehydes, for instance, methylglyoxal (MGO), into the hemithioacetal S-D-Lactoylglutathione using L-glutathione (GSH) as a cofactor. Further substrates of Glo-I are hydroxypyruvaldehyde, hydroxypyruvate aldehyde phosphate, glyoxal, phenylglyoxal, 4,5-dioxovalerate, alkyl and arylglyoxales [4043]. Glo-II hydrolyzes the reaction of S-D-Lactoylglutathione to H2O and D-lactate with regeneration of GSH (Figure 1). Thereby, Glo-I demonstrates the rate limiting step [42, 44], and Glo-II is of subordinate interest in inflammatory research.

Figure 1.

Glyoxalase system. Glyoxalase-I and glyoxalase-II comprise the glyoxalase system for detoxification of MGO. Glutathione is necessary as cofactor and is regenerated by Glo-II. Adapted from [43].

MGO is the main substrate of Glo-I [45] and has been described as a reactive carbonyl compound that is formed as a by-product in glycolysis [46], ketone body metabolism, and threonine catabolism [4749]. MGO leads to cell cytotoxicity in high concentrations through reaction with nucleotides, phospholipids, and proteins [50, 51], resulting in the formation of “advanced glycation end products (AGEs)” and reactive oxygen species (ROS) via AGEs or non-enzymatic reaction with hydrogen peroxide [52]. In this regard, MGO has shown to be involved in various inflammatory processes such as diabetes, aging, renal insufficiency, hypertension, or cancer [6064].

Important MGO-derived AGEs are the non-fluorescent products 5-hydro-5-methylimidazolone (MG-H1) and tetrahydropyrimidine (THP) as well as the major fluorescent product, argpyrimidine [53, 54]. Other non-MGO-derived AGEs comprise Nε-carboxymethyllysine (CML), pyrraline, or pentosidine [55]. The effects of AGEs have been allocated to their antagonistic receptor systems. The receptor for AGEs (RAGE) mediates generation of ROS, inflammation, angiogenesis, and proliferation [56, 57]. In contrast, AGE receptors (AGE-Rs), for instance, AGE-R1, are responsible for detoxification and clearance of AGEs [58]. Upon binding of AGEs to RAGE, various signal transduction pathways are activated. Recent studies showed involvement of the extracellular signal-regulated kinase 1/2 (ERK1/2), phosphoinositide 3-kinase (PI3-K)/protein kinase B (AKT), Janus kinase 2 (JAK2), and Rho GTPases, finally resulting in activation of NF-κB and production of pro-inflammatory cytokines (Figure 3) [59]. In addition, stimulation of RAGE resulted in activation of transforming growth factor (TGF-β) pathway and induced vascular endothelial growth factor (VEGF) overexpression [57].

In the last years, structure and genomic sequence of Glo-I was intensively analyzed. Glo-I is a dimer and consists in mammalian of two identical subunits with a molecular mass of 43–48 kDa [60]. Each subunit contains a zinc ion in its active center, whereas the apoenzyme remains catalytically inactive [45, 61]. The active center of Glo-I is localized between both monomers and comprises two structurally equivalent residues from each domain (Gln-33A, Glu-99A, His-126B, Glu-172B) and two water molecules indicating an octahedral arrangement [54, 62]. The protein sequence of Glo-I consists of 184 amino acids with post-translational modification of N-terminal Met [62].

Genomic analysis revealed three distinct phenotypes of Glo-I: GLO 1-1, GLO 1-2, and GLO 2-2 representing homo- and heterozygous expression of GLO1 und GLO2 [63, 64]. Gene locus of Glo-I is determined on chromosome six between centromere and human leukocyte antigen (HLA)-DR gene [65, 66]. Demographic studies showed higher distribution of GLO1 in Alaska and lower GLO1 allocation in southern and eastern Europe, America, Africa, and India [67].

Genetic sequencing identified association of distinct Glo-I phenotypes and Glo-I SNPs with diabetes [68], cardiovascular diseases [69], schizophrenia [70], autism [71, 72], anxiety [73], and cancer [74, 75]. These findings led to preliminary anti-tumor effects of Glo-I inhibition by siRNA or enzymatic inhibition in different cancer models [7679]. In this regard, well-studied Glo-I inhibitors are S-ρ-bromobenzylglutathione or S-ρ-bromobenzyl-glutathione cyclopentyl diester [77, 80], methotrexate [81], indomethacin [82], troglitazone [83], and flavonoids [84, 85] showing anti-inflammatory and anti-tumor effects. Furthermore, an Glo-I inducer led to improved glycemic control and vascular function in 29 obese patients [86].

In a nutshell, Glo-I is responsible for detoxification of MGO and prevention of MGO-related formation of AGEs and ROS. Therefore, Glo-I and (R)AGE are involved in different pathophysiological inflammatory processes.

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4. Glo-I and R(AGE) in fibrosis, cirrhosis, and NAFLD/NASH

4.1. Glo-I

To date, although Glo-I revealed an important role in inflammation, data about Glo-I in chronic liver disease remain preliminary. In an experimental approach of CCl4-induced cirrhosis, Glo-I was analyzed in vivo and in vitro [87]. Wistar rats were treated with inhalative CCl4 three times a week to induce early cirrhosis (without ascites) after 8 weeks or advanced cirrhosis (with ascites) after 12 weeks. Furthermore, primary liver cells from cirrhotic and noncirrhotic livers were isolated via portal vein perfusion and analysis of Glo-I was performed. Glo-I could be detected in HEP, HSC, and LSEC with highest expression on protein and mRNA levels in HEP. Furthermore, Glo-I expression was reduced in early and advanced cirrhosis in both whole liver and primary liver cells (Figure 2A). The reduction in Glo-I expression was greater with increasing severity of liver disease. Interestingly, the reduction of Glo-I was accompanied by an increase of MGO in cirrhosis (Figure 2B). This accumulation of MGO would lead to increased formation of AGEs and finally augment oxidative stress with ongoing inflammation in chronic liver disease [87]. So far, the reduction of Glo-I with consecutive increase of MGO would provide an explanation for perpetuating liver inflammation in advanced stages of liver disease.

Figure 2.

Glyoxalase-I in CCl4-induced cirrhosis. (A), Glo-I expression was reduced in early (8 week CCl4-treatment) and advanced (12 week CCl4-treatment) cirrhosis in Western blot. Wistar rats were treated three times per week with inhalative CCl4 for induction of cirrhosis. (B), MGO levels were significantly elevated in cirrhosis, indicated by ELISA-analysis. (C), treatment of stellate cells (HSC) for 24 hours with LPS revealed increased production of α-SMA. Cotreatment with Glo-I modulator ethyl pyruvate (EP) abolished the LPS-induced effects. (D), Wistar rats were treated with CCl4 and i.p. EP or saline from week 8 to 12. Sirius red staining indicated significantly less fibrosis in EP-treated animals. * p < 0.05, ** p < 0.01, *** p < 0.001. Adapted from [87].

Furthermore, modulation of Glo-I activity with the anti-inflammatory drug ethyl pyruvate (EP) was performed to analyze impact of Glo-I in initiation and progression of cirrhosis. EP is an α-oxo-carbonic acid and ester of pyruvate. EP came in focus due to anti-inflammatory effects of pyruvate but low stability in aqueous solution [88]. Therefore, EP constitutes a more stable compound and exerts anti-inflammatory and protective effects in a lot of ROS-mediated models [89, 90]. Therefore, a possible molecular basis for the anti-inflammatory effects of EP was assumed to be the inhibition of specific Glo-I activity [91].

Since EP showed protective effects in acute liver failure [9295] and development of fatty liver [96], effect of EP on activation of HSC, as it might occur in initial stadium of cirrhosis, was analyzed. Stimulation of HSC with LPS for 24 hours led to increased levels of α-SMA, indicating activation of HSC and production of collagen deposit. This stimulation could be abrogated by modulation of Glo-I activity by means of EP (Figure 2c). Underlying mechanisms involve stimulation of Nrf2 as well as reduction of NF-κB and ERK/pERK by EP. Additional in vivo experiments revealed reduced collagen deposit in Wistar rats that were treated with CCl4 for 12 weeks and i.p. EP [87]. Furthermore, EP-treated rats revealed significantly less Sirius red staining and consequently less fibrosis compared with controls receiving saline (Figure 2D).

Indeed, anti-inflammatory treatment of several diseases with EP might be a promising future clinical approach. However, EP was analyzed in a clinical trial (phase-II multicenter double-blind placebo-controlled study) in high-risk patients undergoing cardiac surgery with cardiopulmonary bypass. This trial was performed in 13 US hospitals including patients with a Parsonnet risk score > 15 undergoing coronary artery bypass graft and/or cardiac valvular surgery with cardiopulmonary bypass. 102 subjects received either placebo (53) or 7.500 mg (90 mg/kg) EP (49) intravenously followed by five more doses every 6 hours. The primary endpoint was a combination of death, prolonged mechanical ventilation, renal failure, or need of vasoconstrictors. No statistically significant differences were observed between groups with regard to clinical parameters or markers of systemic inflammation [97]. Despite these disappointing results in the first clinical trial, it should be kept in mind that underlying molecular mechanisms in cardiac surgery with cardiopulmonary bypass are complex and at least partly different from ROS models showing protective effects of EP. Another clinical study design, for example, liver fibrosis, pancreatitis, septic shock, might be more promising for this interesting agent.

In summary, targeting Glo-I with EP in cirrhosis revealed an innovative therapeutic target. Nevertheless, further research needs to confirm the aforementioned results in further animal experiments and clinical trials.

4.2. AGEs

In contrast to straightforward evidence of Glo-I in chronic liver disease, several groups analyzed AGEs in liver fibrosis, cirrhosis, and NASH. In cirrhotic patients, limited amount of methylglyoxal-modified proteins were found to be elevated compared to controls [98]. Another study revealed increased levels of CML-AGEs in blood plasma of cirrhotic patients. Also, CML levels correlated with severity of disease [99]. Additional studies confirmed the observations of increased CML levels in fibrosis and cirrhosis [100, 101]. These clinical findings were supported by laboratory analysis: in vitro treatment of HSC with AGEs resulted in enhanced production of oxidative stress providing evidence of AGEs-involvement in fibrosis [102]. Conversely, oxidative stress was found to elevate levels of CML in rats [103] and incubation of HSC with AGEs led to elevation of α-SMA, TGF-β, and collagen-I [104]. In addition, treatment of rat hepatocyte cultures with AGEs reduced cell viability [105]. In an interesting translational study, CML-AGEs were positively correlated with liver stiffness in patients with chronic hepatitis C. In vitro data showed in this study enhanced cell proliferation of HSC treated with BSA-AGEs (CML) and increased production of α-SMA. In contrast, in another study, intraperitoneal administration of AGE-rat serum albumin (CML) revealed increased levels of α-SMA and fibrosis in a model of bile duct ligation [106]. Furthermore, AGEs were found to induce autophagy which subsequently contributes to the fibrosis in patients with chronic hepatitis C [107]. The finding that AGEs were elevated in fibrosis and treatment with AGEs-induced fibrosis led to an interventional approach targeting AGEs to prevent induction of chronic liver disease. Indeed, inhibition of CML resulted in attenuation of CML-induced levels of α-SMA and ROS in HSC [108].

Another model to study fibrosis belongs to metabolic liver diseases: induction of NASH by means of methionine choline deficient diet (MCD). Therefore, hepatic steatosis induced by MCD showed accumulation of CML, and CML was associated with grade of hepatic inflammation and gene expression of inflammatory markers (PAI-1, IL-8, and CRP) [109]. AGEs have also been shown to be involved in etiology of insulin resistance and diabetes [110], and rats fed with a diet rich in AGEs showed elevated oxidative stress and hepatic inflammation leading to NASH [111]. In addition, high dietary AGEs increased hepatic AGEs levels and induced liver injury, inflammation, and liver fibrosis via oxidative stress in activated HSC [112]. Another interesting study investigated the underlying mechanism of AGEs-crosstalk in NASH. AGEs induced NOX2 leading to downregulation of Sirt1/Timp3 and finally resulting in activation of TNF-α converting enzyme and inflammation. These pro-inflammatory cascades finally led to NASH and fibrosis [113]. Interventional studies on AGEs reduction in NASH also revealed promising results. The flavonoid curcumin eliminated the inflammatory effects of AGEs in HSC by interrupting leptin signaling and activating transcription factor Nrf2, which led to the elevation of cellular glutathione levels and the attenuation of oxidative stress [114]. In addition, curcumin decreased activation and proliferation of HSC by AGEs and induced gene expression of AGE-clearing receptor AGE-R1 [115]. The use of the LDL-lowering drug atorvastatin [116] or combination therapy of telmisartan and nateglinide [117] also decreased levels of AGEs in patients with NASH and dyslipidemia, leading to improvement of steatosis, nonalcoholic fatty liver disease activity score, and amelioration of insulin resistance. Another study evaluated effects of aqueous extracts from Solanum nigrum (AESN). AESN could reduce the AGE-induced expression of collagen-II, MMP-2, and α-SMA in HSC. Also, AESN improved insulin resistance and hyperinsulinemia and downregulated lipogenesis, finally preventing fibrosis [118].

Having the auspicious and conclusive effects of AGEs-lowering drugs in fibrosis in mind, it should be noted that mainly CML-AGEs were investigated. Therefore, it should be considered that CML-AGEs are rarely produced via reaction of MGO but are rather formed in lipoxidation and glycoxidation independent of MGO [119].

4.3. RAGE

The pattern recognition receptor RAGE belongs to the immunoglobulin superfamily with a molecular mass of 47–55 kDa. RAGE expression is stimulated under inflammatory conditions such as diabetes, cardiovascular diseases, or cancer [120]. RAGE has been shown to be activated by MGO- and non-MGO-derived AGEs as well as multiple ligands. Binding to RAGE results in activation of transcription factors, such as NF-κB [121], leading to the release of pro-inflammatory cytokines.

Indeed, several studies revealed participation of RAGE in fibrosis: Upon stimulation with AGE-rat serum albumin containing mainly CML, levels of RAGE, α-SMA, hydroxyproline, and Sirius red were elevated in a fibrosis model of bile duct ligation (BDL) [106, 122]. Interestingly, RAGE was found to be predominantly expressed in HSC. RAGE was stimulated in HSC during transformation to myofibroblasts, and RAGE was colocalized with α-SMA and induced by TGF-β. In addition, RAGE was expressed in filopodial membranes of myofibroblasts suggesting a role of RAGE in spreading and migration of activated HSC in fibrogenesis [123]. Further analysis provided evidence for crosstalk of RAGE and TGF-β: AGEs-induced upregulation of RAGE induced TGF-β, TNF-α, and IL-8. Interestingly, RAGE also stimulated anti-inflammatory cytokines IL-2 and IL-4 indicating a negative feedback mechanism and inhibitory crosstalk between TGF-β and RAGE [124]. In the next step, effect of RAGE inhibition on inflammation and fibrosis was discovered. First, curcumin was found to reduce, besides its AGEs-lowering effects, the gene expression of RAGE via elevation of PPAR-γ [125]. Furthermore, RAGE expression was diminished by means of RAGE siRNA in primary rat HSC resulting in downregulation of IL-6, TNF-α, and TGF-β [126]. In a following in vivo study, effects of repetitive RAGE siRNA in an olive oil model of fibrosis were analyzed. RAGE siRNA was injected twice weekly in the tail vein of Sprague-Dawley rats. After 6 weeks, reduced expressions of RAGE, TNF-α, IL-6, extracellular matrix, hyaluronic acid, and procollagen III were found. Also, activation of HSC and NF-κB was reduced in siRNA-treated animals attenuating the initiation and progression of fibrosis [127]. Additional studies revealed protective effects of anti-RAGE antibodies in BDL-induced acute liver injury [128, 129].

Growing evidence for implication of RAGE in fibrosis was found in NASH. Methionine choline deficient (MCD) diet caused steatosis and increased RAGE, inflammation, and fibrosis [112]. Recently, fatty acids stimulated CML accumulation and subsequently elicited RAGE induction [109]. Another group found upregulation of RAGE in the liver of aged mice with consecutive elevated oxidative stress shown by analysis of malondialdehyde. Blocking of RAGE by anti-RAGE-antibody revealed in this study prolonged survival of animals [130].

In a nutshell, various studies confirmed implication of Glo-I and (R)AGE in inflammatory liver disease and fibrosis. Especially targeting Glo-I in cirrhosis highlighted the meaning of MGO-induced liver damage and offers new therapeutic opportunities. Nevertheless, further research in this topic will uncover the exact role of Glo-I in chronic liver disease and possible translation to clinical approach (see Figure 3).

Figure 3.

Impact of Glo-I and (R)AGE in cirrhosis. MGO reacts with proteins, nucleotides, and lipids leading to formation of AGEs. AGEs bind to RAGE and activate several signal pathways (including MAPK (ERK1/2, p38, JNK), PI3-K/AKT, and JAK2/STAT1), finally leading to activation of NF-κB. In a consequence, the induced production of TGF-β and pro-inflammatory cytokines activate quiescent stellate cells. HSC transform to myofibroblasts and produce pro-fibrotic factors and collagen. The collagen deposition in the liver will lead to fibrosis and finally cirrhosis. Reduction of Glo-I will perpetuate both, initiation and progression of cirrhosis due to increase of MGO and a vicious circle of disease. MGO: methylglyoxal, AGEs: advanced glycation end products, RAGE: receptor for advanced glycation end products, Glo-I: glyoxalase-I, HSC: hepatic stellate cells, MAPK: mitogen-activated protein kinase, PI3-K: phosphoinositide 3-kinase, AKT: protein kinase B, JAK2: Janus kinase 2, STAT1: signal transducer and activator of transcription-1, JNK: c-Jun N-terminal kinase, and NF-κB: nuclear factor-κB.

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Abbreviations

AGEsadvanced glycation end products
AKTprotein kinase B
EPethyl pyruvate
ET-1endothelin-1
Glo-Iglyoxalase-I
Glo-IIglyoxalase-II
GSHL-glutathione
HCChepatocellular carcinoma
HEPhepatocytes
HSChepatic stellate cells
JAK2Janus kinase 2
JNKc-Jun N-terminal kinase
KCKupffer cells
LSECliver sinusoidal endothelial cells
MAPKmitogen-activated protein kinase
MCDmethionine choline deficient diet
MG-H15-hydro-5-methylimidazolone
MGOmethylglyoxal
NAFLD/NASHnon-alcoholic fatty liver disease/steatohepatitis
NF-κBnuclear factor-κB
NOnitric oxide
PI3-Kphosphoinositide 3-kinase
RAGEreceptor for advanced glycation end products
sRAGEsoluble form of RAGE
ROSreactive oxygen species
STAT1signal transducer and activator of transcription-1
TGF-βtransforming growth factor beta
THPtetrahydropyrimidine

References

  1. 1. Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. Journal of Hepatology. 2013;59:160-168
  2. 2. Novo E, Cannito S, Paternostro C, et al. Cellular and molecular mechanisms in liver fibrogenesis. Archives of Biochemistry and Biophysics. 2014;548:20-37
  3. 3. Dobbs BR, Rogers GW, Xing HY, et al. Endotoxin-induced defenestration of the hepatic sinusoidal endothelium: A factor in the pathogenesis of cirrhosis? Liver. 1994;14:230-233
  4. 4. Fernandez M, Semela D, Bruix J, et al. Angiogenesis in liver disease. Journal of Hepatology. 2009;50:604-620
  5. 5. Bosch J. Vascular deterioration in cirrhosis: The big picture. Journal of Clinical Gastroenterology. 2007;41(Suppl 3):S247-S253
  6. 6. Rockey DC. Vascular mediators in the injured liver. Hepatology. 2003;37:4-12
  7. 7. Groszmann RJ. Nitric oxide and hemodynamic impairment. Digestion. 1998;59(Suppl 2):6-7
  8. 8. Iwakiri Y. Endothelial dysfunction in the regulation of cirrhosis and portal hypertension. Liver International. 2012;32:199-213
  9. 9. Abraldes JG, Iwakiri Y, Loureiro-Silva M, et al. Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2006;290:G980-G987
  10. 10. Groszmann RJ. Hyperdynamic circulation of liver disease 40 years later: Pathophysiology and clinical consequences. Hepatology. 1994;20:1359-1363
  11. 11. Zipprich A, Loureiro-Silva MR, Jain D, et al. Nitric oxide and vascular remodeling modulate hepatic arterial vascular resistance in the isolated perfused cirrhotic rat liver. Journal of Hepatology. 2008;49:739-745
  12. 12. Friedman SL. Mechanisms of disease: Mechanisms of hepatic fibrosis and therapeutic implications. Nature Clinical Practice Gastroenterology & Hepatology. 2004;1:98-105
  13. 13. Friedman SL. Liver fibrosis: From bench to bedside. Journal of Hepatology. 2003;38(Suppl 1):S38-S53
  14. 14. Breitkopf K, Nagy LE, Beier JI, et al. Current experimental perspectives on the clinical progression of alcoholic liver disease. Alcoholism Clinical and Experimental Research. 2009;33:1647-1655
  15. 15. Hoek JB, Pastorino JG. Cellular signaling mechanisms in alcohol-induced liver damage. Seminars in Liver Disease. 2004;24:257-272
  16. 16. Nagy LE. Recent insights into the role of the innate immune system in the development of alcoholic liver disease. Experimental Biology and Medicine (Maywood). 2003;228:882-890
  17. 17. Hritz I, Mandrekar P, Velayudham A, et al. The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology. 2008;48:1224-1231
  18. 18. Zhao XJ, Dong Q, Bindas J, et al. TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol. Journal of Immunology. 2008;181:3049-3056
  19. 19. Roychowdhury S, McMullen MR, Pritchard MT, et al. An early complement-dependent and TLR-4-independent phase in the pathogenesis of ethanol-induced liver injury in mice. Hepatology. 2009;49:1326-1334
  20. 20. Cubero FJ, Nieto N. Kupffer cells and alcoholic liver disease. Revista Espanola de Eenfermedades Digestivas. 2006;98:460-472
  21. 21. Cubero FJ, Urtasun R, Nieto N. Alcohol and liver fibrosis. Seminars in Liver Disease. 2009;29:211-221
  22. 22. Seki E, De MS, Osterreicher CH, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nature Medicine. 2007;13:1324-1332
  23. 23. Quiroz SC, Bucio L, Souza V, et al. Effect of endotoxin pretreatment on hepatic stellate cell response to ethanol and acetaldehyde. Journal of Gastroenterology and Hepatology. 2001;16:1267-1273
  24. 24. Bai T, Lian LH, Wu YL, et al. Thymoquinone attenuates liver fibrosis via PI3K and TLR4 signaling pathways in activated hepatic stellate cells. International Immunopharmacology. 2013;15:275-281
  25. 25. Novo E, Parola M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair. 2008;1:5
  26. 26. Jaruga B, Hong F, Kim WH, et al. Chronic alcohol consumption accelerates liver injury in T cell-mediated hepatitis: alcohol disregulation of NF-kappaB and STAT3 signaling pathways. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2004;287:G471-G479
  27. 27. Zima T, Kalousova M. Oxidative stress and signal transduction pathways in alcoholic liver disease. Alcoholism Clinical and Experimental Research. 2005;29:110S-115S
  28. 28. Kureishi Y, Kobayashi S, Amano M, et al. Rho-associated kinase directly induces smooth muscle contraction through myosin light chain phosphorylation. Journal of Biological Chemistry. 1997;272:12257-12260
  29. 29. Jagavelu K, Routray C, Shergill U, et al. Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liver. Hepatology. 2010;52:590-601
  30. 30. Ding BS, Nolan DJ, Butler JM, et al. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature. 2010;468:310-315
  31. 31. Loureiro-Silva MR, Iwakiri Y, Abraldes JG, et al. Increased phosphodiesterase-5 expression is involved in the decreased vasodilator response to nitric oxide in cirrhotic rat livers. Journal of Hepatology. 2006;44:886-893
  32. 32. Yokomori H, Oda M, Ogi M, et al. Enhanced expression of endothelial nitric oxide synthase and caveolin-1 in human cirrhosis. Liver. 2002;22:150-158
  33. 33. Iwakiri Y, Tsai MH, McCabe TJ, et al. Phosphorylation of eNOS initiates excessive NO production in early phases of portal hypertension. American Journal of Physiology: Heart and Circulatory Physiology. 2002;282:H2084-H2090
  34. 34. Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: A role for nitric oxide? Lancet. 1991;337:776-778
  35. 35. Malyshev E, Tazi KA, Moreau R, et al. Discrepant effects of inducible nitric oxide synthase modulation on systemic and splanchnic endothelial nitric oxide synthase activity and expression in cirrhotic rats. Journal of Gastroenterology and Hepatology. 2007;22: 2195-2201
  36. 36. Mezey E, Potter JJ, Rennie-Tankersley L, et al. A randomized placebo controlled trial of vitamin E for alcoholic hepatitis. Journal of Hepatology. 2004;40:40-46
  37. 37. Stewart S, Prince M, Bassendine M, et al. A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis. Journal of Hepatology. 2007;47:277-283
  38. 38. Moreno C, Langlet P, Hittelet A, et al. Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: A randomized multicenter controlled trial. Journal of Hepatology. 2010;53:1117-1122
  39. 39. Dakin HD, Dudley HW. An enzyme concerned with the formation of hydroxy acids from ketonic aldehydes. Journal of Biological Chemistry. 1913;14:155-157
  40. 40. Weaver RH, Lardy HA. Synthesis and some biochemical properties of phosphohydroxypyruvic aldehyde and of 3-phosphoglyceryl glutathione thiol ester. Journal of Biological Chemistry. 1961;236:313-317
  41. 41. Vander Jagt DL. The glyoxalase system. In: Glutathione: Chemical, Biochemical and Medical Aspects. New York: Wiley-Interscience; 1989. pp. 597-641
  42. 42. Mannervik B. Glyoxalase I. In: Enzymatic Basis of Detoxification. Vol. 2. New York: Academic Press; 1980. pp. 263-293
  43. 43. Thornalley PJ. The glyoxalase system in health and disease. Molecular Aspects of Medicine. 1993;14:287-371
  44. 44. Racker E. The mechanism of action of glyoxalase. Journal of Biological Chemistry. 1951;190:685-696
  45. 45. Thornalley PJ. The glyoxalase system: New developments towards functional characterization of a metabolic pathway fundamental to biological life. Biochemical Journal. 1990;269:1-11
  46. 46. Ohmori S, Mori M, Shiraha K, et al. Biosynthesis and degradation of methylglyoxal in animals. Progress in Clinical Biological Research. 1989;290:397-412
  47. 47. Ray S, Ray M. Formation of methylglyoxal from aminoacetone by amine oxidase from goat plasma. Journal of Biological Chemistry. 1983;258:3461-3462
  48. 48. Casazza JP, Felver ME, Veech RL. The metabolism of acetone in rat. Journal of Biological Chemistry. 1984;259:231-236
  49. 49. Phillips SA, Thornalley PJ. The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal. European Journal of Biochemistry. 1993;212:101-105
  50. 50. Vaca CE, Fang JL, Conradi M, et al. Development of a 32P-postlabelling method for the analysis of 2'-deoxyguanosine-3'-monophosphate and DNA adducts of methylglyoxal. Carcinogenesis. 1994;15:1887-1894
  51. 51. Lo TW, Westwood ME, McLellan AC, et al. Binding and modification of proteins by methylglyoxal under physiological conditions. A kinetic and mechanistic study with N alpha-acetylarginine, N alpha-acetylcysteine, and N alpha-acetyllysine, and bovine serum albumin. Journal of Biological Chemistry. 1994;269:32299-32305
  52. 52. Nakayama M, Saito K, Sato E, et al. Radical generation by the non-enzymatic reaction of methylglyoxal and hydrogen peroxide. Redox Report. 2007;12:125-133
  53. 53. Oya T, Hattori N, Mizuno Y, et al. Methylglyoxal modification of protein. Chemical and immunochemical characterization of methylglyoxal-arginine adducts. Journal of Biological Chemistry. 1999;274:18492-18502
  54. 54. Thornalley PJ. Glyoxalase I: Structure, function and a critical role in the enzymatic defence against glycation. Biochemical Society Transactions. 2003;31:1343-1348
  55. 55. Singh R, Barden A, Mori T, et al. Advanced glycation end-products: A review. Diabetologia. 2001;44:129-146
  56. 56. Schmidt AM, Yan SD, Yan SF, et al. The biology of the receptor for advanced glycation end products and its ligands. Biochimica et Biophysica Acta. 2000;1498:99-111
  57. 57. Piperi C, Goumenos A, Adamopoulos C, et al. AGE/RAGE signalling regulation by miRNAs: Associations with diabetic complications and therapeutic potential. International Journal of Biochemistry & Cell Biology. 2015;60C:197-201
  58. 58. Lu C, He JC, Cai W, et al. Advanced glycation endproduct (AGE) receptor 1 is a negative regulator of the inflammatory response to AGE in mesangial cells. Proceedings of the National Academy of Sciences USA. 2004;101:11767-11772
  59. 59. Xiang Y, Li Q, Li M, et al. Ghrelin inhibits AGEs-induced apoptosis in human endothelial cells involving ERK1/2 and PI3K/Akt pathways. Cell Biochemistry and Function. 2011;29:149-155
  60. 60. Han LP, Schimandle CM, Davison LM, et al. Comparative kinetics of Mg2+-, Mn2+-, Co2+-, and Ni2+-activated glyoxalase I. Evaluation of the role of the metal ion. Biochemistry. 1977;16:5478-5484
  61. 61. Sellin S, Eriksson LE, Aronsson AC, et al. Octahedral metal coordination in the active site of glyoxalase I as evidenced by the properties of Co(II)-glyoxalase I. Journal of Biological Chemistry. 1983;258:2091-2093
  62. 62. Cameron AD, Olin B, Ridderstrom M, et al. Crystal structure of human glyoxalase I: Evidence for gene duplication and 3D domain swapping. EMBO Journal. 1997;16:3386-3395
  63. 63. Kompf J, Bissbort S, Gussmann S, et al. Polymorphism of red cell glyoxalase I (EI: 4.4.1.5); a new genetic marker in man. Investigation of 169 mother-child combinations. Humangenetik. 1975;27:141-143
  64. 64. Kompf J, Bissbort S, Ritter H. Red cell glyoxalase i (E.C.: 4.4.1.5): Formal genetics and linkage relations. Humangenetik. 1975;28:249-251
  65. 65. Bender K, Grzeschik KH. Assignment of the genes for human glyoxalase I to chromosome 6 and for human esterase D to chromosome 13. Cytogenetics and Cell Genetics. 1976;16:93-96
  66. 66. Kompf J, Bissbort S. Confirmation of linkage between the loci for HL-A and glyoxalase I. Human Genetics. 1976;32:197-198
  67. 67. Thornalley PJ. Population genetics of human glyoxalases. Heredity. 1991;67(Pt 2):139-142
  68. 68. McCann VJ, Davis RE, Welborn TA, et al. Glyoxalase phenotypes in patients with diabetes mellitus. Australian and New Zealand Journal of Medicine. 1981;11:380-382
  69. 69. Gale CP, Futers TS, Summers LK. Common polymorphisms in the glyoxalase-1 gene and their association with pro-thrombotic factors. Diabetes and Vascular Disease Research 2004;1:34-39
  70. 70. Bangel FN, Yamada K, Arai M, et al. Genetic analysis of the glyoxalase system in schizophrenia. Neuro-Psychopharmacology and Biological Psychiatry. 2015;59:105-110
  71. 71. Barua M, Jenkins EC, Chen W, et al. Glyoxalase I polymorphism rs2736654 causing the Ala111Glu substitution modulates enzyme activity--implications for autism. Autism Research. 2011;4:262-270
  72. 72. Junaid MA, Kowal D, Barua M, et al. Proteomic studies identified a single nucleotide polymorphism in glyoxalase I as autism susceptibility factor. American Journal of Medical Genetics Part A. 2004;131:11-17
  73. 73. Williams R, Lim JE, Harr B, et al. A common and unstable copy number variant is associated with differences in Glo1 expression and anxiety-like behavior. PLoS One. 2009;4:e4649
  74. 74. Santarius T, Bignell GR, Greenman CD, et al. GLO1-A novel amplified gene in human cancer. Genes Chromosomes Cancer. 2010;49:711-725
  75. 75. Shafie A, Xue M, Thornalley PJ, et al. Copy number variation of glyoxalase I. Biochemical Society Transactions. 2014;42:500-503
  76. 76. Thornalley PJ, Tisdale MJ. Inhibition of proliferation of human promyelocytic leukaemia HL60 cells by S-D-lactoylglutathione in vitro. Leukemia Research. 1988;12:897-904
  77. 77. Thornalley PJ, Edwards LG, Kang Y, et al. Antitumour activity of S-p-bromobenzylgluta thione cyclopentyl diester in vitro and in vivo. Inhibition of glyoxalase I and induction of apoptosis. Biochemical Pharmacology. 1996;51:1365-1372
  78. 78. Baunacke M, Horn LC, Trettner S, et al. Exploring glyoxalase 1 expression in prostate cancer tissues: Targeting the enzyme by ethyl pyruvate defangs some malignancy-associated properties. Prostate. 2014;74:48-60
  79. 79. Birkenmeier G, Hemdan NY, Kurz S, et al. Ethyl pyruvate combats human leukemia cells but spares normal blood cells. PLoS One. 2016;11:e0161571
  80. 80. Lo TW, Thornalley PJ. Inhibition of proliferation of human leukaemia 60 cells by diethyl esters of glyoxalase inhibitors in vitro. Biochemical Pharmacology. 1992;44:2357-2363
  81. 81. Bartyik K, Turi S, Orosz F, et al. Methotrexate inhibits the glyoxalase system in vivo in children with acute lymphoid leukaemia. European Journal of Cancer. 2004;40:2287-2292
  82. 82. Sato S, Kwon Y, Kamisuki S, et al. Polyproline-rod approach to isolating protein targets of bioactive small molecules: Isolation of a new target of indomethacin. Journal of the American Chemical Society. 2007;129:873-880
  83. 83. Wu L, Eftekharpour E, Davies GF, et al. Troglitazone selectively inhibits glyoxalase I gene expression. Diabetologia. 2001;44:2004-2012
  84. 84. Takasawa R, Takahashi S, Saeki K, et al. Structure-activity relationship of human GLO I inhibitory natural flavonoids and their growth inhibitory effects. Bioorganic & Medicinal Chemistry. 2008;16:3969-3975
  85. 85. Santel T, Pflug G, Hemdan NY, et al. Curcumin inhibits glyoxalase 1: A possible link to its anti-inflammatory and anti-tumor activity. PLoS One. 2008;3:e3508
  86. 86. Xue M, Weickert MO, Qureshi S, et al. Improved glycemic control and vascular function in overweight and obese subjects by glyoxalase 1 inducer formulation. Diabetes. 2016;65:2282-2294
  87. 87. Hollenbach M, Thonig A, Pohl S, et al. Expression of glyoxalase-I is reduced in cirrhotic livers: A possible mechanism in development of cirrhosis. PLoS One. 2017;12(2):e0171260. DOI: 10.1371/journal.pone.0171260
  88. 88. Fink MP. Ethyl pyruvate: A novel anti-inflammatory agent. Journal of Internal Medicine. 2007;261:349-362
  89. 89. Fink MP. Ethyl pyruvate: A novel treatment for sepsis. Novartis Foundation Symposium. 2007;280:147-156
  90. 90. Fink MP. Ethyl pyruvate. Current Opinion in Anaesthesiology. 2008;21:160-167
  91. 91. Hollenbach M, Hintersdorf A, Huse K, et al. Ethyl pyruvate and ethyl lactate down-regulate the production of pro-inflammatory cytokines and modulate expression of immune receptors. Biochemical Pharmacology. 2008;76:631-644
  92. 92. Wang LW, Wang LK, Chen H, et al. Ethyl pyruvate protects against experimental acute-on-chronic liver failure in rats. World Journal of Gastroenterology. 2012;18:5709-5718
  93. 93. Yang R, Han X, Delude RL, et al. Ethyl pyruvate ameliorates acute alcohol-induced liver injury and inflammation in mice. Journal of Laboratory and Clinical Medicine. 2003;142:322-331
  94. 94. Yang R, Shaufl AL, Killeen ME, et al. Ethyl pyruvate ameliorates liver injury secondary to severe acute pancreatitis. Journal of Surgical Research. 2009;153:302-309
  95. 95. Yang R, Zou X, Koskinen ML, et al. Ethyl pyruvate reduces liver injury at early phase but impairs regeneration at late phase in acetaminophen overdose. Critical Care. 2012;16:R9
  96. 96. Olek RA, Ziolkowski W, Flis DJ, et al. The effect of ethyl pyruvate supplementation on rat fatty liver induced by a high-fat diet. Journal of Nutritional Science and Vitaminology (Tokyo). 2013;59:232-237
  97. 97. Bennett-Guerrero E, Swaminathan M, Grigore AM, et al. A phase II multicenter double-blind placebo-controlled study of ethyl pyruvate in high-risk patients undergoing cardiac surgery with cardiopulmonary bypass. Journal of Cardiothoracic and Vascular Anesthesia. 2009;23:324-329
  98. 98. Ahmed N, Thornalley PJ, Luthen R, et al. Processing of protein glycation, oxidation and nitrosation adducts in the liver and the effect of cirrhosis. Journal of Hepatology. 2004;41:913-919
  99. 99. Sebekova K, Kupcova V, Schinzel R, et al. Markedly elevated levels of plasma advanced glycation end products in patients with liver cirrhosis - amelioration by liver transplantation. Journal of Hepatology. 2002;36:66-71
  100. 100. Yagmur E, Tacke F, Weiss C, et al. Elevation of Nepsilon-(carboxymethyl)lysine-modified advanced glycation end products in chronic liver disease is an indicator of liver cirrhosis. Clinical Biochemistry. 2006;39:39-45
  101. 101. Zuwala-Jagiello J, Pazgan-Simon M, Simon K, et al. Elevated advanced oxidation protein products levels in patients with liver cirrhosis. Acta biochimica Polonica. 2009;56:679-685
  102. 102. Guimaraes EL, Empsen C, Geerts A, et al. Advanced glycation end products induce production of reactive oxygen species via the activation of NADPH oxidase in murine hepatic stellate cells. Journal of Hepatology. 2010;52:389-397
  103. 103. Lorenzi R, Andrades ME, Bortolin RC, et al. Oxidative damage in the liver of rats treated with glycolaldehyde. International Journal of Toxicology. 2011;30:253-258
  104. 104. Iwamoto K, Kanno K, Hyogo H, et al. Advanced glycation end products enhance the proliferation and activation of hepatic stellate cells. Journal of Gastroenterology. 2008;43:298-304
  105. 105. Hayashi N, George J, Takeuchi M, et al. Acetaldehyde-derived advanced glycation end-products promote alcoholic liver disease. PLoS One. 2013;8:e70034
  106. 106. Goodwin M, Herath C, Jia Z, et al. Advanced glycation end products augment experimental hepatic fibrosis. Journal of Gastroenterology and Hepatology. 2013;28:369-376
  107. 107. He Y, Zhu J, Huang Y, et al. Advanced glycation end product (AGE)-induced hepatic stellate cell activation via autophagy contributes to hepatitis C-related fibrosis. Acta Diabetologica. 2015;52:959-969
  108. 108. Hsu WH, Lee BH, Hsu YW, et al. Peroxisome proliferator-activated receptor-gamma activators monascin and rosiglitazone attenuate carboxymethyllysine-induced fibrosis in hepatic stellate cells through regulating the oxidative stress pathway but independent of the receptor for advanced glycation end products signaling. Journal of Agricultural and Food Chemistry. 2013;61:6873-6879
  109. 109. Gaens KH, Niessen PM, Rensen SS, et al. Endogenous formation of Nepsilon-(carboxymethyl)lysine is increased in fatty livers and induces inflammatory markers in an in vitro model of hepatic steatosis. Journal of Hepatology. 2012;56:647-655
  110. 110. Vlassara H. Recent progress in advanced glycation end products and diabetic complications. Diabetes. 1997;46(Suppl 2):S19-S25
  111. 111. Patel R, Baker SS, Liu W, et al. Effect of dietary advanced glycation end products on mouse liver. PLoS One. 2012;7:e35143
  112. 112. Leung C, Herath CB, Jia Z, et al. Dietary glycotoxins exacerbate progression of experimental fatty liver disease. Journal of Hepatology. 2014;60:832-838
  113. 113. Jiang JX, Chen X, Fukada H, et al. Advanced glycation endproducts induce fibrogenic activity in nonalcoholic steatohepatitis by modulating TNF-alpha-converting enzyme activity in mice. Hepatology. 2013;58:1339-1348
  114. 114. Tang Y, Chen A. Curcumin eliminates the effect of advanced glycation end-products (AGEs) on the divergent regulation of gene expression of receptors of AGEs by interrupting leptin signaling. Laboratory Investigation. 2014;94:503-516
  115. 115. Lin J, Tang Y, Kang Q, et al. Curcumin eliminates the inhibitory effect of advanced glycation end-products (AGEs) on gene expression of AGE receptor-1 in hepatic stellate cells in vitro. Laboratory Investigation. 2012;92:827-841
  116. 116. Kimura Y, Hyogo H, Yamagishi S, et al. Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH. Journal of Gastroenterology. 2010;45:750-757
  117. 117. Miura K, Kitahara Y, Yamagishi S. Combination therapy with nateglinide and vildagliptin improves postprandial metabolic derangements in Zucker fatty rats. Hormone and Metabolic Research. 2010;42:731-735
  118. 118. Tai CJ, Choong CY, Shi YC, et al. Solanum nigrum protects against hepatic fibrosis via suppression of hyperglycemia in high-fat/ethanol diet-induced rats. Molecules. 2016;21:269
  119. 119. Fu MX, Requena JR, Jenkins AJ, et al. The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions. Journal of Biological Chemistry. 1996;271:9982-9986
  120. 120. Yamagishi S, Matsui T. Role of receptor for advanced glycation end products (RAGE) in liver disease. European Journal of Medical Research. 2015;20:15
  121. 121. Barbezier N, Tessier FJ, Chango A. Receptor of advanced glycation endproducts RAGE/AGER: An integrative view for clinical applications. Annales de Biologie Clinique (Paris). 2014;72:669-680
  122. 122. Lohwasser C, Neureiter D, Popov Y, et al. Role of the receptor for advanced glycation end products in hepatic fibrosis. World Journal of Gastroenterology. 2009;15:5789-5798
  123. 123. Fehrenbach H, Weiskirchen R, Kasper M, et al. Up-regulated expression of the receptor for advanced glycation end products in cultured rat hepatic stellate cells during transdifferentiation to myofibroblasts. Hepatology. 2001;34:943-952
  124. 124. Serban AI, Stanca L, Geicu OI, et al. RAGE and TGF-beta1 cross-talk regulate extracellular matrix turnover and cytokine synthesis in AGEs exposed fibroblast cells. PLoS One. 2016;11:e0152376
  125. 125. Lin J, Tang Y, Kang Q, et al. Curcumin inhibits gene expression of receptor for advanced glycation end-products (RAGE) in hepatic stellate cells in vitro by elevating PPARgamma activity and attenuating oxidative stress. British Journal of Pharmacology. 2012;166:2212-2227
  126. 126. Xia JR, Chen TT, Li WD, et al. Inhibitory effect of receptor for advanced glycation end product specific small interfering RNAs on the development of hepatic fibrosis in primary rat hepatic stellate cells. Molecular Medicine Reports. 2015;12:569-574
  127. 127. Cai XG, Xia JR, Li WD, et al. Anti-fibrotic effects of specific-siRNA targeting of the receptor for advanced glycation end products in a rat model of experimental hepatic fibrosis. Molecular Medicine Reports. 2014;10:306-314
  128. 128. Xia P, Deng Q, Gao J, et al. Therapeutic effects of antigen affinity-purified polyclonal anti-receptor of advanced glycation end-product (RAGE) antibodies on cholestasis-induced liver injury in rats. European Journal of Pharmacology. 2016;779:102-110
  129. 129. Kao YH, Lin YC, Tsai MS, et al. Involvement of the nuclear high mobility group B1 peptides released from injured hepatocytes in murine hepatic fibrogenesis. Biochimica et Biophysica Acta. 2014;1842:1720-1732
  130. 130. Kuhla A, Trieglaff C, Vollmar B. Role of age and uncoupling protein-2 in oxidative stress, RAGE/AGE interaction and inflammatory liver injury. Experimental Gerontology. 2011;46:868-876

Written By

Marcus Hollenbach

Submitted: January 11th, 2017 Reviewed: March 9th, 2017 Published: July 5th, 2017