Galectin-3 ablation protects mice from diet-induced NASH: A major scavenging role for galectin-3 in liver

Iacobini, Carla; Menini, Stefano; Ricci, C; Fantauzzi, Claudia Blasetti; Scipioni, Angela; Salvi, Laura; Cordone, Samantha; Delucchi, Francesca; Sérino, Matteo; Federici, Massimo; Pricci, Flavia; Pugliese, Giuseppe

doi:10.1016/j.jhep.2010.09.020

Cited by 135 publications

(115 citation statements)

References 31 publications

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“…Recent evidence shows that activation of the IL-17 axis in obesitydriven NAFLD has an important role in the progression of liver steatosis to NASH (30). The data of attenuated liver inflammation in LGALS3 -/-mice fed obesogenic HFD in this study are in agreement with the data in the study of the atherogenic diet model of NASH (15). Importantly, in HFD-fed LGALS3 -/-mice, hepatic IL-33, ST2 (IL-33 receptor) and IL-13 mRNA expression and IL-33 and IL-13 levels were lower in liver homogenates compared with WT mice (Supplementary Figures 4A, B).…”

Section: Discussionsupporting

confidence: 91%

Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis

Jeftic

Jovičić

Pantic

et al. 2015

Mol Med

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The importance of Galectin-3 (Gal-3) in obesity-associated liver pathology is incompletely defined. To dissect the role of Gal-3 in fibrotic nonalcoholic steatohepatitis (NASH), Gal-3-deficient (LGALS3 -/-) and wild-type (LGALS3 +/+ ) C57Bl/6 mice were placed on an obesogenic high fat diet (HFD, 60% kcal fat) or standard chow diet for 12 and 24 wks. Compared to WT mice, HFD-fed LGALS3 -/-mice developed, in addition to increased visceral adiposity and diabetes, marked liver steatosis, which was accompanied with higher expression of hepatic PPAR-γ, Cd36, Abca-1 and FAS. However, as opposed to LGALS3 -/-mice, hepatocellular damage, inflammation and fibrosis were more extensive in WT mice which had an elevated number of mature myeloid dendritic cells, proinflammatory CD11b + Ly6C hi monocytes/macrophages in liver, peripheral blood and bone marrow, and increased hepatic CCL2, F4/80, CD11c, TLR4, CD14, NLRP3 inflammasome, IL-1β and NADPH-oxidase enzymes mRNA expression. Thus, obesitydriven greater steatosis was uncoupled with attenuated fibrotic NASH in Gal-3-deficient mice. HFD-fed WT mice had a higher number of hepatocytes that strongly expressed IL-33 and hepatic CD11b genotypes, albeit to a significantly lower extent in LGALS3 -/-mice, which was associated with less numerous hepatic IL-13-expressing CD11b + cells. The present study provides evidence of a novel role for Gal-3 in regulating IL-33-dependent liver fibrosis. adipose tissue and islets where dendritic cells (DCs) and macrophages play important roles (11). The data on the effect of Gal-3 ablation in liver steatosis/inflammation are controversial. Nomoto et al. (13) showed that Gal-3-deficient mice spontaneously developed steatosis at six months of age and that a lack of Gal-3 led to greater steatosis and liver injury in the model of CDAA diet-induced NASH (14). On the other hand, in a study by Iacobini et al. (15) Gal-3 null mice fed an atherogenic diet were resistant to the development of steatosis and NASH. In the liver, Gal-3 is highly expressed in Kupffer cells and its expression is increased during hepatocellular damage (16). The essential step in hepatic inflammation and fibrogenesis is CCL2-mediated monocyte recruitment (17,18). Resident and recruited liver macrophages may be polarized toward classically activated macrophages (M1), which promote survival of hepatic myofibroblasts by secreted TNF-α and IL-1β, and, alternatively, macrophages that express the Th2-type cytokines (M2), including IL-13, which directly stimulates collagen synthesis in myofibroblasts (19)(20)(21). Macrophage-derived Gal-3 has been shown to promote myofibroblast activation in liver fibrosis (22,23). The disruption of the Gal-3 gene was reported to block TGF-β mediated myofibroblast activation and procollagen expression and markedly attenuated CCl 4 -induced liver fibrosis in mice (22). Interleukin-33 (IL-33), a damage-associated molecular pattern (DAMP) molecule, could induce IL-13 production by macrophages to promote type 2 immunity (24). IL-33 has a profibrogenic role ...

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Section: Discussionsupporting

confidence: 91%

Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis

Jeftic

Jovičić

Pantic

et al. 2015

Mol Med

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“…Furthermore, circulating galectin-3 levels predict renal function decline and cardiovascular and all-cause mortality in patients with CKD (85). Consistent with epidemiological data, functional galectin-3 manipulation has shown important proinflammatory and profibrotic effects of this lectin (26,83,84). On this basis, pharmacological galectin-3 inhibition with small-molecule competitive inhibitors, including GR-MD-02 (galactoarabino-rhamnogalaturonan), GM-CT-01 (galactomannan), and Nacetyllactosamine, prevents hypertensive nephropathy (86) and reverses diet-induced NASH and cirrhosis (87).…”

Section: Targeting Molecular Effectors Of Inflammation and Fibrosissupporting

confidence: 63%

“…COX, cyclooxygenase; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-related kinase; G6PD, glucose-6-phosphate dehydrogenase; Glt-Px, glutathione peroxidase; Glt-R, glutathione reductase; GST, glutathione S-transferase; HPC, hepatic progenitor cells; iNOS, inducible nitric oxide synthase; IRS, insulin receptor substrate; NKT, natural killer T; NOS, nitric oxide synthase; PAI-1, plasminogen activator inhibitor 1; TXN-R, thioredoxin reductase. and renal disease (26,84). Furthermore, circulating galectin-3 levels predict renal function decline and cardiovascular and all-cause mortality in patients with CKD (85).…”

Section: Targeting Molecular Effectors Of Inflammation and Fibrosismentioning

confidence: 99%

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

et al. 2016

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Chronic kidney disease (CKD) is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease (CVD). ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and mortality in CKD remains unchanged. These data suggest that key pathogenetic mechanisms underlying CKD progression go unaffected by current treatments. Growing evidence suggests that nonalcoholic fatty liver disease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets. Common nutritional conditions predisposing to both NAFLD and CKD include excessive fructose intake and vitamin D deficiency. Modulation of nuclear transcription factors regulating key pathways of lipid metabolism, inflammation, and fibrosis, including peroxisome proliferatoractivated receptors and farnesoid X receptor, is advancing to stage III clinical development. The relevance of epigenetic regulation in the pathogenesis of NAFLD and CKD is also emerging, and modulation of microRNA21 is a promising therapeutic target. Although single antioxidant supplementation has yielded variable results, modulation of key effectors of redox regulation and molecular sensors of intracellular energy, nutrient, or oxygen status show promising preclinical results. Other emerging therapeutic approaches target key mediators of inflammation, such as chemokines; fibrogenesis, such as galectin-3; or gut dysfunction through gut microbiota manipulation and incretin-based therapies. Furthermore, NAFLD per se affects CKD through lipoprotein metabolism and hepatokine secretion, and conversely, targeting the renal tubule by sodium-glucose cotransporter 2 inhibitors can improve both CKD and NAFLD. Implications for the treatment of NAFLD and CKD are discussed in light of this new therapeutic armamentarium. EPIDEMIOLOGICAL EVIDENCE LINKING NAFLD AND CKDChronic kidney disease (CKD) affects up to 8% of the world's adult population, with its prevalence increasing in an aging population beset by lifestyle-associated diseases such as obesity, the metabolic syndrome, diabetes, hypertension, and smoking (1). CKD may progress to end-stage renal disease (ESRD) and is an important cardiovascular disease (CVD) risk factor. Importantly, most patients with CKD die as a result of CVD before renal replacement therapy is initiated (1).There is potential for improving recognition and treatment of CKD. In the Third National Health and Nutrition Survey, awareness among patients with stage 3 CKD was ,8% (1). Furthermore, ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and all-cause mortality remains unchanged in the CKD population (2). These data suggest that key pathogenetic mechanisms underlying

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“…Consistently, liver AGE and ALE levels and RAGE expression were decreased in galectin-3 deficient mice as opposed to wild-type. Moreover, galectin-3 silencing reduced the uptake of the AGE CML by liver sinusoidal endothelial cells, the main site of AGE removal, thus indicating that this lectin [86], at variance with scavenger receptor A and CD36 [87,88], is a major scavenger receptor in the liver. Therefore, in galectin-3 deficient mice, the reduced hepatic uptake of AGEs/ALES could have played a role both in the prevention of NASH and the increase of circulating levels of these byproducts.…”

Section: Galectin-3 As a Disease Mediator: Animal Studiesmentioning

confidence: 98%

Galectin-3 in diabetic patients

Pugliese

Iacobini

Ricci

et al. 2014

Clinical Chemistry and Laboratory Medicine (CCLM)

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Galectin-3 is a versatile molecule which exerts several and sometimes opposite functions in various pathophysiological processes. Recently, galectin-3 has gained attention as a powerful predictor of heart failure and mortality, thus becoming a useful prognostic marker in clinical practice. Moreover, though not specifically investigated in diabetic cohorts, plasma levels of galectin-3 correlated with the prevalence of diabetes and related metabolic conditions, thus suggesting that pharmacological blockade of this lectin might be successful for treating heart failure especially in subjects suffering from these disorders. Indeed, galectin-3 is considered not only as a marker of heart failure, but also as a mediator of the disease, due to its pro-fibrotic action, though evidence comes mainly from studies in galectin-3 deficient mice. However, these studies have provided contrasting results, with either attenuation or acceleration of organ fibrosis and inflammation, depending on the experimental setting and particularly on the levels of advanced glycation endproducts (AGEs)/advanced lipoxidation endproducts (ALEs), of which galectin-3 is a scavenging receptor. In fact, under conditions of increased AGE/ALE levels, galectin-3 ablation was associated with tissue-specific outcomes, reflecting the AGE/ALE-receptor function of this lectin. Conversely, in experimental models of acute inflammation and fibrosis, galectin-3 deficiency resulted in attenuation of tissue injury. There is a need for prospective studies in diabetic patients specifically investigating the relation of galectin-3 levels with complications and for further animal studies in order to establish the effective role of this lectin in organ damage before considering its pharmacological blockade in the clinical setting.

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Galectin-3 ablation protects mice from diet-induced NASH: A major scavenging role for galectin-3 in liver

Cited by 135 publications

References 31 publications

Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis

Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities

Galectin-3 in diabetic patients

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