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World J Gastroenterol. Nov 28, 2016; 22(44): 9706-9717
Published online Nov 28, 2016. doi: 10.3748/wjg.v22.i44.9706
Galectin-3 and IL-33/ST2 axis roles and interplay in diet-induced steatohepatitis
Nada Pejnovic, Ilija Jeftic, Nemanja Jovicic, Nebojsa Arsenijevic, Miodrag L Lukic
Nada Pejnovic, Ilija Jeftic, Nemanja Jovicic, Nebojsa Arsenijevic, Miodrag L Lukic, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
Author contributions: Pejnovic N, Jeftic I and Jovicic N wrote the manuscript and performed the experiments on dietary-induced animal steatohepatitis; Arsenijevic N and Lukic ML checked and revised the manuscript.
Supported by Swiss Science Foundation, No. SCOPES, IZ73Z0_152407.
Conflict-of-interest statement: No potential conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Miodrag L Lukic, MD, PhD, Professor, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia. miodrag.lukic@medf.kg.ac.rs
Telephone: +38-134-306800 Fax: +38-134-306800-112
Received: June 28, 2016
Peer-review started: June 30, 2016
First decision: July 29, 2016
Revised: September 2, 2016
Accepted: September 14, 2016
Article in press: September 14, 2016
Published online: November 28, 2016
Processing time: 150 Days and 20.4 Hours
Abstract

Immune reactivity and chronic low-grade inflammation (metaflammation) play an important role in the pathogenesis of obesity-associated metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD), a spectrum of diseases that include liver steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from hepatic steatosis to NASH and fibrosis through the development of proinflammatory and profibrotic processes in the liver, including increased hepatic infiltration of innate and adaptive immune cells, altered balance of cytokines and chemokines, increased reactive oxygen species generation and hepatocellular death. Experimental models of dietary-induced NAFLD/NASH in mice on different genetic backgrounds or knockout mice with different immune reactivity are used for elucidating the pathogenesis of NASH and liver fibrosis. Galectin-3 (Gal-3), a unique chimera-type β-galactoside-binding protein of the galectin family has a regulatory role in immunometabolism and fibrogenesis. Mice deficient in Gal-3 develop pronounced adiposity, hyperglycemia and hepatic steatosis, as well as attenuated liver inflammation and fibrosis when fed an obesogenic high-fat diet. Interleukin (IL)-33, a member of the IL-1 cytokine family, mediates its effects through the ST receptor, which is present on immune and nonimmune cells and participates in immunometabolic and fibrotic disorders. Recent evidence, including our own data, suggests a protective role for the IL-33/IL-33R (ST2) signaling pathway in obesity, adipose tissue inflammation and atherosclerosis, but a profibrotic role in NASH development. The link between Gal-3 and soluble ST2 in myocardial fibrosis and heart failure progression has been demonstrated and we have recently shown that Gal-3 and the IL-33/ST2 pathway interact and both have a profibrotic role in diet-induced NASH. This review discusses the current evidence on the roles of Gal-3 and the IL-33/ST2 pathway and their interplay in obesity-associated hepatic inflammation and fibrogenesis that may be of interest in the development of therapeutic interventions to prevent and/or reverse obesity-associated hepatic inflammation and fibrosis.

Keywords: Galectin-3; Liver fibrosis; Interleukin-33; ST2; Nonalcoholic steatohepatitis

Core tip: Obesity-associated chronic low-grade inflammation (metaflammation) plays an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Galectin-3 (Gal-3), a β-galactoside-binding protein, plays a regulatory role in metaflammation and tissue fibrosis. The Interleukin (IL)-33/ST2 pathway has a protective role in obesity and adipose tissue inflammation and promotes liver fibrosis. The characteristics of dietary-induced NASH differ in mice on different genetic backgrounds and Gal-3 and ST2 (IL-33R) knockout mice. In this report, we review current evidence on the roles of Gal-3 and the IL-33/ST2 pathway and their interplay in obesity-associated hepatic inflammation and fibrogenesis that may be of interest in the development of therapeutic interventions.