Galectin-3 inhibition as a potential therapeutic target in non-alcoholic steatohepatitis liver fibrosis

This review centered around the evolving role of the galectin-3 and the hepatic Gal3+ macrophage at the center of the liver fibrotic pathway. Cell to cell interactions between the hepatocyte, the macrophage, and the stellate cells initiate the transformation of the stellate cell into a myofibroblast that lays down collagen in the ECM. Genomics, transcriptomics, proteomics, immunohistochemistry staining, and live cell to cell mapping have confirmed the vital role of galectin-3 in liver fibrosis. The concept of the ‘galectin-3 fibrosome’ has been illuminated, and the role of the galectin-3 positive macrophage in liver fibrosis continues to evolve. The picture is filling in but is by no means complete. A confounding factor for those researching this topic is that the medical literature is confused by older terms still being employed for the same process, both for galectin-3, and for the hepatic Gal3+ macrophage. The author believes an international consensus needs to be achieved on nomenclature as this field moves forward. It is apparent that galectin-3 inhibition for liver fibrosis and cirrhosis will continue to be a fertile target of clinical research. Given galectin-3’s role in HCC and HCC metastatic spread, it is intriguing to speculate that galectin-3 inhibition might have protective effects against HCC development in cirrhosis, as well as a potential future role in adjunctive HCC therapy. In the next few years, data from upcoming galectin-3 inhibition trials will determine whether the future of NASH therapy includes this promising antifibrotic approach.

The most advanced inhibitors currently in trials are belapectin and GB1107. Belapectin is a large molecule galactoarabino-rhamnogalacturonan polysaccharide inhibitor derived from natural sources. Post hoc analysis of a phase 2 belapectin study in compensated cirrhosis showed that belapectin prevented esophageal varices formation in a subgroup analysis of patients without esophageal varices at baseline, and reduced hepatic venous pressure gradient after 52 weeks of therapy[ 50 ]. A follow up international adaptive P2b/3 trial is now ongoing using the clinical endpoint of preventing esophageal varices based on endoscopic evaluation[ 51 ]. GB1107 is a small molecule thiogalactoside oral inhibitor targeting the CRD. It is advancing in P2 with a trial in cirrhotics and a first in human study with GB1211, an analogue of GB1107, is proceeding into a P2 study with cirrhosis of all etiologies[ 52 ].

Non-alcoholic steatohepatitis (NASH) is an aggressive form of nonalcoholic fatty liver disease characterized by hepatic steatosis, ballooning hepatocytes, inflammation of hepatic lobules, and excessive deposition of fibrotic tissue. If left untreated, NASH may progress to cirrhosis and hepatocellular carcinoma (HCC), which are major causes of morbidity and mortality[ 1 , 2 ]. The risks for HCC are particularly worrisome in the subpopulation of NASH with diabetes, obesity[ 3 ], hypertension and dyslipidemia[ 4 ]. Thus far, there are no approved pharmacotherapeutics for the treatment of NASH and the only curative treatment for cirrhosis and early-stage HCC is a liver transplant. NASH has a complex pathogenesis that is triggered by multiple metabolic factors, including insulin resistance, genetic factors, and lifestyle issues such as unbalanced excessive caloric intake and lack of exercise[ 5 ]. Classically, the disease has been divided into early and late stages, and investigative pharmacotherapeutics target different pathogenic metabolic pathways to gain resolution of steatohepatitis or regression of fibrosis, or ideally both processes. Regardless of the etiology or the pathway, the changeover from nonalcoholic fatty liver disease (NAFLD) to NASH leads to liver fibrosis and cirrhosis, via the transformation of the hepatic stellate cell (HSC) to an activated myofibroblast that lays down collagen. In liver fibrosis, the interaction of HSCs with other cells is complex. Liver sinusoidal endothelial cells modulate HSCs quiescence as well as fibrosis regression in the homeostatic state[ 6 ]. In the fibrotic process, apoptotic hepatocytes increase the inflammatory response and activate macrophages. Chronic liver injury leads to continuous HSCs activation, first via the resident liver macrophage, the Kupffer cell, and then via myeloid derived liver macrophages which then promote extracellular matrix (ECM) accumulation and tissue structure remodeling and resulting in progressive liver fibrosis[ 7 ]. The transforming growth factor (TGF)-β1 has been viewed as the major profibrogenic cytokine released by the liver cell upon injury, turning the HSC into a myofibroblast. A comprehensive review of liver fibrosis has recently been published[ 8 ], as well as a review of the signaling pathways and drugs targeting the various pathways in non-alcoholic steatohepatitis[ 9 ]. There are many disease processes where the galectin-3 protein has been implicated[ 10 ]. Recent data has shown galectin-3 as a direct causative agent in diverse diseases such as endometriosis[ 11 ], cardiac fibrosis and atrial fibrillation[ 12 ], and Alzheimer’s disease[ 13 ]. Galectin-3 plays a leading role in cancer progression and in the tumor microenvironment[ 14 ]. In HCC, overexpression of galectin-1 and galectin-3 have been noted[ 15 ], and galectin-3 favors tumor metastases via activation of β-catenin signaling[ 16 ]. In cirrhosis, galectin-3 has been proven to be a biomarker, in combination with other scores, to discriminate advanced cirrhosis and predict post-transplant infectious complications[ 17 ]. High tissue expression of galectin-3 was also associated with the risk of chronic liver disease and worse overall survival[ 18 ]. Blood levels of galectin-3 have not correlated as a biomarker in NASH, since other background diseases such as heart disease can raise galectin-3 levels on their own[ 19 ]. This review will focus on the role of galectin-3 in the liver fibrosis associated with NASH.

The author acknowledges Dr. Pol Boudes for reviewing this manuscript and Dr. Zachary Goodman for providing the galectin-3 antibody histological images.