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Review
. 2017 Nov 20;18(11):2466.
doi: 10.3390/ijms18112466.

The Role of Glyoxalase-I (Glo-I), Advanced Glycation Endproducts (AGEs), and Their Receptor (RAGE) in Chronic Liver Disease and Hepatocellular Carcinoma (HCC)

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Free PMC article
Review

The Role of Glyoxalase-I (Glo-I), Advanced Glycation Endproducts (AGEs), and Their Receptor (RAGE) in Chronic Liver Disease and Hepatocellular Carcinoma (HCC)

Marcus Hollenbach. Int J Mol Sci. .
Free PMC article

Abstract

Glyoxalase-I (Glo-I) and glyoxalase-II (Glo-II) comprise the glyoxalase system and are responsible for the detoxification of methylglyoxal (MGO). MGO is formed non-enzymatically as a by-product, mainly in glycolysis, and leads to the formation of advanced glycation endproducts (AGEs). AGEs bind to their receptor, RAGE, and activate intracellular transcription factors, resulting in the production of pro-inflammatory cytokines, oxidative stress, and inflammation. This review will focus on the implication of the Glo-I/AGE/RAGE system in liver injury and hepatocellular carcinoma (HCC). AGEs and RAGE are upregulated in liver fibrosis, and the silencing of RAGE reduced collagen deposition and the tumor growth of HCC. Nevertheless, data relating to Glo-I in fibrosis and cirrhosis are preliminary. Glo-I expression was found to be reduced in early and advanced cirrhosis with a subsequent increase of MGO-levels. On the other hand, pharmacological modulation of Glo-I resulted in the reduced activation of hepatic stellate cells and therefore reduced fibrosis in the CCl₄-model of cirrhosis. Thus, current research highlighted the Glo-I/AGE/RAGE system as an interesting therapeutic target in chronic liver diseases. These findings need further elucidation in preclinical and clinical studies.

Keywords: AGEs; CCl4; cirrhosis; ethyl pyruvate; fibrosis; methylglyoxal.

Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Glo-I, AGEs, and RAGE in cirrhosis. MGO reacts with proteins, nucleotides, and lipids, leading to the formation of AGEs. AGEs bind to RAGE and stimulate signal pathways (including MAPK (ERK1/2, p38, JNK), PI3-K/AKT, and JAK2/STAT1). This stimulation results in the activation of NF-κB, followed by the production of TGF-β and pro-inflammatory cytokines. These cytokines activate quiescent stellate cells, which transform to myofibroblasts and produce profibrotic factors and collagen. The collagen deposition in the liver will lead to fibrosis and finally cirrhosis. The reduction of Glo-I will perpetuate both the initiation and progression of cirrhosis through an increase of MGO and a vicious circle of disease. MGO is detoxified via Glo-I to S-d-Lactoylglutathione which is finally converted to d-Lactate by Glo-II. MGO: methylglyoxal. AGEs: advanced glycation endproducts. RAGE: receptor for advanced glycation endproducts. Glo-I: glyoxalase-I. Glo-II: glyoxalase II. ROS: reactive oxygen species. HSC: hepatic stellate cells. MAPK: mitogen-activated protein kinase. ERK1/2: Extracellular-signal regulated kinase. PI3-K: phosphoinositide 3-kinase. AKT: protein kinase B. JAK2: Januskinase 2. STAT1: signal transducer and activator of transcription-1. JNK: c-Jun N-terminal kinase: NF-κB: nuclear factor-κB. TGF-β: Transforming growth factor β. TNF-α: Tumor necrosis factor α. IL-1: Interleukin-1.
Figure 2
Figure 2
Glyoxalase-I in CCl4-induced cirrhosis. (A) Wistar rats were treated for 12 weeks, three times per week, with inhalative CCl4 to induce advanced cirrhosis. Explanted livers were fixed in 4% formaline, dehydrated, and embedded. Immunostaining for Glo-I with DAB compound was performed as previously described [83]. Overview sections (5× magnification, upper line) and sections at 20× magnification (lower line) showed reduced expression of Glo-I in advanced cirrhosis; (B) Wistar rats were treated with CCl4 and intraperitoneally (i.p.) EP 40 mg/kg body weight daily or saline from weeks 8–12. Explanted livers were fixed, dehydrated, and embedded. Sirius red staining was performed as previously described [83]. Sections showed reduced amount of Sirius red upon EP treatment. Scale bars: 400 µm (A, upper line), 100 µm (A, lower line, B).
Figure 2
Figure 2
Glyoxalase-I in CCl4-induced cirrhosis. (A) Wistar rats were treated for 12 weeks, three times per week, with inhalative CCl4 to induce advanced cirrhosis. Explanted livers were fixed in 4% formaline, dehydrated, and embedded. Immunostaining for Glo-I with DAB compound was performed as previously described [83]. Overview sections (5× magnification, upper line) and sections at 20× magnification (lower line) showed reduced expression of Glo-I in advanced cirrhosis; (B) Wistar rats were treated with CCl4 and intraperitoneally (i.p.) EP 40 mg/kg body weight daily or saline from weeks 8–12. Explanted livers were fixed, dehydrated, and embedded. Sirius red staining was performed as previously described [83]. Sections showed reduced amount of Sirius red upon EP treatment. Scale bars: 400 µm (A, upper line), 100 µm (A, lower line, B).

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