Hierarchical and selective roles of galectins in hepatocarcinogenesis, liver fibrosis and inflammation of hepatocellular carcinoma

Table 2 Galectins in inflammation-associated liver injury

Galectin member	Experimental model		Role	Effects	Ref.
Galectin-1	Hepatitis induced by injection of Con A		Protective	Prevents both liver injury and T-helper cell liver infiltration, induces apoptosis of Con A-activated T cells, suppresses plasma levels of TNF and IFN-γ	[89]
	Inflammation-induced chronic cholestatic hepatitis at an early age, and HCC at later age (Mdr2-KO mice)		Protective	Galectin-1 is up-regulated in Mdr2-KO/B6 strain at early age	[91]
	Galectin-1-KO mice in the context of Con A-induced autoimmune hepatitis		Protective	Con A up-regulates galectin-1 in galectin-1-KO/B6 and Mdr2-KO/FVB strains. Endogenous galectin-1 selectively protects liver in the B6, but not in the FVB genetic background. It probably determines strain-specific differences in the course of chronic hepatitis and HCC development in the Mdr2-KO model	[91]
Galectin-3	NASH model	Galectin-3-KO mice	Protective	Develops NAFLD/NASH spontaneously with aging	[140,141]
		CDAA diet-induced NAFLD/NASH in galectin-3-KO mice	Protective	Galectin-3 deficiency causes more severe hepatic injury and alterations in the expression of genes associated with carcinogenesis and lipid metabolism	[142]
		Atherogenic diet-induced NASH in galectin-3-KO mice	Promotes disease severity	Attenuates NASH: inhibits HSC-driven fibrosis, reduces inflammatory-cell infiltration and hepatocyte apoptosis, acts as a major scavenger receptor involved in ALE/AGE uptake by the liver	[143]
	Human liver tissues		Protective	Negative expression of galectin-3 in normal hepatocytes, strong staining for galectin-3 in hepatocytes from patients with steatosis hepatitis, hepatitis, cholestasis and cirrhosis	[145]
	Acute liver failure induced by APAP- hepatotoxicity in galectin-3-KO mice		Perpetuates liver injury	In wild type mice, galectin-3 is up-regulated in liver infiltrating macrophages. In galectin-3 deficient mice the pro-inflammatory M1-type macrophages subpopulation, the classical macrophage activation markers iNOS, TNF and IL-12 and pro-inflammatory chemokines are reduced	[147,148]
	Hepatitis induced by injection of Con A in galectin-3-KO mice		Pro-inflammatory	Galectin-3 deficiency reduces the number of T lymphocytes, B lymphocytes, dendritic cells, NK and NKT cells and enhances apoptosis of mononuclear cells	[149]
	Con A-induced liver injury in wild type mice pretreated with a selective inhibitor of galectin-3 (TD139)		Pro-inflammatory	TD139 attenuates liver injury, reduces the number of CD4+ and CD8+ T cells, favors the influx of IL-10-producing CD4+ T cells in the liver, decreases serum levels of IFN-γ, IL-17 and IL-4	[149]
Galectin-9	Blockade of the TIM-3/galectin-9 pathway using an anti-TIM-3 or anti-galectin-9 mAb in a context of liver IRI		Protective	Blockade of the TIM-3/galectin-9 pathway increases hepatocellular damage, local neutrophil infiltration, T cell and macrophage accumulation and liver cell apoptosis. Increases IFN-γ production by Con A-stimulated spleen T cells and augmented TNF and IL-6 production by Con A-stimulated macrophages/T cells	[190]
	Single injection of galectin-9 in the murine model of liver injury induced by Con A		Protective	Eliminates activated CD4+ effector T cells, prevents the synthesis and/or release of proinflammatory cytokine	[191]
	Mouse model of diet-induced NAFLD treated with galectin-9		Limits the inflammatory response	Induces apoptosis of NKT cells, also interacts with TIM-3-expressing Kupffer cells to induce secretion of IL-15, thus promoting NKT cell proliferation	[195]

ALE/AGE: Advanced lipoxidation and glycation end products; APAP: Acetaminophen; CDAA: Choline-deficient L-amino-acid; Con A: Concanavalin A; HSC: Hepatic stellate cells; IFN-γ: Interferon γ; IL: Interleukin; iNOS: Inducible isoform nitric oxide synthase; IRI: Ischemia and reperfusion injury; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; NK: Natural killer; NKT: NK T cells; TIM-3: T-cell immunoglobulin mucin domain 3; TNF: Tumor necrosis factor; HCC: Hepatocellular carcinoma; KO: Knockout.