Topic Highlight
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Dec 27, 2014; 6(12): 880-893
Published online Dec 27, 2014. doi: 10.4254/wjh.v6.i12.880
Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies
Masayoshi Takeuchi, Jun-ichi Takino, Akiko Sakasai-Sakai, Takanobu Takata, Tadashi Ueda, Mikihiro Tsutsumi, Hideyuki Hyogo, Sho-ichi Yamagishi
Masayoshi Takeuchi, Akiko Sakasai-Sakai, Takanobu Takata, Tadashi Ueda, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa 920-0293, Japan
Jun-ichi Takino, Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan
Mikihiro Tsutsumi, Department of Hepatology, Kanazawa Medical University, Uchinada-machi, Ishikawa 920-0293, Japan
Hideyuki Hyogo, Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima 734-8551, Japan
Sho-ichi Yamagishi, Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
Author contributions: All of the authors contributed to this paper.
Supported by The Japan Society for the Promotion of Science (JSPS) KAKENHI Grant, No. 19300254, 22300264 and 25282029 (Takeuchi M); Kanazawa Medical University, No. SR2012-04 (Tsutsumi M); the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Regional Innovation Strategy Support Program (Takeuchi M)
Correspondence to: Dr. Masayoshi Takeuchi, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa 920-0293, Japan.
Telephone: +81-076-2188456 Fax: +81-076-2863652
Received: August 12, 2014
Revised: October 22, 2014
Accepted: October 28, 2014
Published online: December 27, 2014

Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease around the world. It includes a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis (NASH) and can lead to fibrosis, cirrhosis, liver failure, and/or hepatocellular carcinoma. NAFLD is also associated with other medical conditions such as obesity, diabetes mellitus (DM), metabolic syndrome, hypertension, insulin resistance, hyperlipidemia, and cardiovascular disease (CVD). In diabetes, chronic hyperglycemia contributes to the development of both macro- and microvascular conditions through a variety of metabolic pathways. Thus, it can cause a variety of metabolic and hemodynamic conditions, including upregulated advanced glycation end-products (AGEs) synthesis. In our previous study, the most abundant type of toxic AGEs (TAGE); i.e., glyceraldehyde-derived AGEs, were found to make a significant contribution to the pathogenesis of DM-induced angiopathy. Furthermore, accumulating evidence suggests that the binding of TAGE with their receptor (RAGE) induces oxidative damage, promotes inflammation, and causes changes in intracellular signaling and the expression levels of certain genes in various cell populations including hepatocytes and hepatic stellate cells. All of these effects could facilitate the pathogenesis of hypertension, cancer, diabetic vascular complications, CVD, dementia, and NASH. Thus, inhibiting TAGE synthesis, preventing TAGE from binding to RAGE, and downregulating RAGE expression and/or the expression of associated effector molecules all have potential as therapeutic strategies against NASH. Here, we examine the contributions of RAGE and TAGE to various conditions and novel treatments that target them in order to prevent the development and/or progression of NASH.

Keywords: Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis, Advanced glycation end-products, Toxic advanced glycation end-products, Receptor for advanced glycation end-products, Toxic advanced glycation end-products-receptor for advanced glycation end-products system, Diabetes mellitus, Cardiovascular disease, Dietary fructose, Dietary advanced glycation end-products

Core tip: Toxic advanced glycation end-products (TAGE) synthesis is increased by non-alcoholic steatohepatitis (NASH), and patients with NASH exhibit significantly increased serum and hepatic TAGE concentrations. Interactions between TAGE and the receptor for advanced glycation end-products (RAGE) have been suggested to cause oxidative stress and increase the fibrogenic potential of cultured human hepatic stellate cells. Therefore, TAGE signaling via RAGE and the resultant synthesis of reactive oxygen species might play a role in the worsening of hepatic pathology seen in NASH. These observations led us to suggest that extracellular and intracellular TAGE are involved in the pathogenesis of NASH.