Background & Aims: Excess fatty acid oxidation and generation of reactive carbonyls with formation of advanced lipoxidation endproducts (ALEs) is involved in nonalcoholic steatohepatitis (NASH) by triggering inflammation, hepatocyte injury, and fibrosis. This study aimed at verifying the hypothesis that ablation of the ALE-receptor galectin-3 prevents experimental NASH by reducing receptor-mediated ALE clearance and downstream events. Methods: Galectin-3-deficient (Lgals3(-1-)) and wild type (Lgals3(+/+)) mice received an atherogenic diet or standard chow for 8 months. Liver tissue was analyzed for morphology, inflammation, cell and matrix turnover, lipid metabolism, ALEs, and ALE-receptors. Results: Steatosis was significantly less pronounced in Lgals3(-1-) than Lgals3(+/+) animals on atherogenic diet. NASH, invariably detected in Lgals3(+/+) mice, was observed, to a lower extent, only in 3/8 Lgals3(-1-) mice, showing less inflammatory, degenerative, and fibrotic phenomena than Lgals3(+/+) mice. This was associated with higher circulating ALE levels and lower tissue ALE accumulation and expression of other ALE-receptors. Up-regulation of hepatic fatty acid synthesis and oxidation, inflammatory cell infiltration, pro-inflammatory cytokines, endoplasmic reticulum stress, hepatocyte apoptosis, myofibroblast transdifferentiation, and impaired Akt phosphorylation were also significantly attenuated in Lgals3(-1-) animals. Galectin-3 silencing in liver endothelial cells resulted in reduced N(epsilon)-carboxymethyllysine-modified albumin uptake and ALE-receptor expression. Conclusions: Galectin-3 ablation protects from diet-induced NASH by decreasing hepatic ALE accumulation, with attenuation of inflammation, hepatocyte injury, and fibrosis. It also reduced up-regulation of lipid synthesis and oxidation causing less fat deposition, oxidative stress, and possibly insulin resistance. These data suggest that galectin-3 is a major receptor involved in ALE uptake by the liver. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Galectin-3 ablation protects mice from diet-induced NASH. A major scavenging role for galectin-3 in liver / Iacobini, Carla; Menini, Stefano; Ricci, Carlo; C., Blasetti Fantauzzi; BLASETTI FANTAUZZI, Claudia; Angela, Scipioni; Salvi, Laura; Cordone, Samantha; Francesca, Delucchi; Matteo, Serino; Massimo, Federici; Flavia, Pricci; Pugliese, Giuseppe. - In: JOURNAL OF HEPATOLOGY. - ISSN 0168-8278. - 54:5(2011), pp. 1-9. [10.1016/j.jhep.2010.09.020]

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

IACOBINI, carla
Co-primo
;
MENINI, Stefano
Co-primo
;
RICCI, Carlo;BLASETTI FANTAUZZI, CLAUDIA;SALVI, LAURA;CORDONE, Samantha;PUGLIESE, Giuseppe
2011

Abstract

Background & Aims: Excess fatty acid oxidation and generation of reactive carbonyls with formation of advanced lipoxidation endproducts (ALEs) is involved in nonalcoholic steatohepatitis (NASH) by triggering inflammation, hepatocyte injury, and fibrosis. This study aimed at verifying the hypothesis that ablation of the ALE-receptor galectin-3 prevents experimental NASH by reducing receptor-mediated ALE clearance and downstream events. Methods: Galectin-3-deficient (Lgals3(-1-)) and wild type (Lgals3(+/+)) mice received an atherogenic diet or standard chow for 8 months. Liver tissue was analyzed for morphology, inflammation, cell and matrix turnover, lipid metabolism, ALEs, and ALE-receptors. Results: Steatosis was significantly less pronounced in Lgals3(-1-) than Lgals3(+/+) animals on atherogenic diet. NASH, invariably detected in Lgals3(+/+) mice, was observed, to a lower extent, only in 3/8 Lgals3(-1-) mice, showing less inflammatory, degenerative, and fibrotic phenomena than Lgals3(+/+) mice. This was associated with higher circulating ALE levels and lower tissue ALE accumulation and expression of other ALE-receptors. Up-regulation of hepatic fatty acid synthesis and oxidation, inflammatory cell infiltration, pro-inflammatory cytokines, endoplasmic reticulum stress, hepatocyte apoptosis, myofibroblast transdifferentiation, and impaired Akt phosphorylation were also significantly attenuated in Lgals3(-1-) animals. Galectin-3 silencing in liver endothelial cells resulted in reduced N(epsilon)-carboxymethyllysine-modified albumin uptake and ALE-receptor expression. Conclusions: Galectin-3 ablation protects from diet-induced NASH by decreasing hepatic ALE accumulation, with attenuation of inflammation, hepatocyte injury, and fibrosis. It also reduced up-regulation of lipid synthesis and oxidation causing less fat deposition, oxidative stress, and possibly insulin resistance. These data suggest that galectin-3 is a major receptor involved in ALE uptake by the liver. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
2011
inflammation; steatosis; fibrosis; oxidative stress; advanced lipoxidation endproducts
01 Pubblicazione su rivista::01a Articolo in rivista
Galectin-3 ablation protects mice from diet-induced NASH. A major scavenging role for galectin-3 in liver / Iacobini, Carla; Menini, Stefano; Ricci, Carlo; C., Blasetti Fantauzzi; BLASETTI FANTAUZZI, Claudia; Angela, Scipioni; Salvi, Laura; Cordone, Samantha; Francesca, Delucchi; Matteo, Serino; Massimo, Federici; Flavia, Pricci; Pugliese, Giuseppe. - In: JOURNAL OF HEPATOLOGY. - ISSN 0168-8278. - 54:5(2011), pp. 1-9. [10.1016/j.jhep.2010.09.020]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/377405
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