title: Microvesicles released from fat-laden cells promote activation of hepatocellular NLRP3 inflammasome: A pro-inflammatory link between lipotoxicity and non-alcoholic steatohepatitis.
abstract: Non-Alcoholic Fatty Liver Disease (NAFLD) is a major form of chronic liver disease in the general population in relation to its high prevalence among overweight/obese individuals and patients with diabetes type II or metabolic syndrome. NAFLD can progress to steatohepatitis (NASH), fibrosis and cirrhosis and end-stage of liver disease but mechanisms involved are still incompletely characterized. Within the mechanisms proposed to mediate the progression of NAFLD, lipotoxicity is believed to play a major role. In the present study we provide data suggesting that microvesicles (MVs) released by fat-laden cells undergoing lipotoxicity can activate NLRP3 inflammasome following internalization by either cells of hepatocellular origin or macrophages. Inflammasome activation involves NF-kB-mediated up-regulation of NLRP3, pro-caspase-1 and pro-Interleukin-1, then inflammasome complex formation and Caspase-1 activation leading finally to an increased release of IL-1β. Since the release of MVs from lipotoxic cells and the activation of NLRP3 inflammasome have been reported to occur in vivo in either clinical or experimental NASH, these data suggest a novel rational link between lipotoxicity and increased inflammatory response.
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Cannito
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Morello
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bocca
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Foglia
authors.affiliation: Department of Drug Science and Technology, University of Torino, Torino, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Benetti
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Novo
authors.affiliation: Department of Drug Science and Technology, University of Torino, Torino, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Chiazza
authors.affiliation: Department of Drug Science and Technology, University of Torino, Torino, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Rogazzo
authors.affiliation: Department of Drug Science and Technology, University of Torino, Torino, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Fantozzi
authors.affiliation: Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA, United States of America.
authors.forename: Davide
authors.initials: D
authors.lastname: Povero
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Center for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Sutti
authors.affiliation: Department of Medical Sciences, Division of Gastroenterology, University of Torino, Torino, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bugianesi
authors.affiliation: Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA, United States of America.
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Center for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Albano
authors.affiliation: Department of Drug Science and Technology, University of Torino, Torino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Parola
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology; D011498:Protein Precursors / Q000378:metabolism
chemical_list: D058847:Inflammasomes; D007375:Interleukin-1; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011498:Protein Precursors; C043830:interleukin 1 precursor; D020170:Caspase 1