title: Galectin-3 ablation protects mice from diet-induced NASH: a major scavenging role for galectin-3 in liver.
abstract: OBJECTIVE
  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(-/-)) 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(-/-) than Lgals3(+/+) animals on atherogenic diet. NASH, invariably detected in Lgals3(+/+) mice, was observed, to a lower extent, only in 3/8 Lgals3(-/-) 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(-/-) animals. Galectin-3 silencing in liver endothelial cells resulted in reduced N(ε)-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.
authors.affiliation: Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Iacobini
authors.forename: Stefano
authors.initials: S
authors.lastname: Menini
authors.forename: Carlo
authors.initials: C
authors.lastname: Ricci
authors.forename: Claudia
authors.initials: C
authors.lastname: Blasetti Fantauzzi
authors.forename: Angela
authors.initials: A
authors.lastname: Scipioni
authors.forename: Laura
authors.initials: L
authors.lastname: Salvi
authors.forename: Samantha
authors.initials: S
authors.lastname: Cordone
authors.forename: Francesca
authors.initials: F
authors.lastname: Delucchi
authors.forename: Matteo
authors.initials: M
authors.lastname: Serino
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
authors.forename: Flavia
authors.initials: F
authors.lastname: Pricci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pugliese
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D004036:Diet, Atherogenic; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D037502:Galectin 3 / Q000235:genetics* / Q000378:metabolism*; D020868:Gene Silencing; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: D018955:CD36 Antigens; D037502:Galectin 3; C485095:Lgals3 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic