title: Resistin as an intrahepatic cytokine: overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells.
abstract: Obesity and insulin resistance accelerate the progression of fibrosis during chronic liver disease. Resistin antagonizes insulin action in rodents, but its role in humans is still controversial. The aims of this study were to investigate resistin expression in human liver and to evaluate whether resistin may affect the biology of activated human hepatic stellate cells (HSCs), key modulators of hepatic fibrogenesis. Resistin gene expression was low in normal human liver but was increased in conditions of severe fibrosis. Up-regulation of resistin during chronic liver damage was confirmed by immunohistochemistry. In a group of patients with alcoholic hepatitis, resistin expression correlated with inflammation and fibrosis, suggesting a possible action on HSCs. Exposure of cultured HSCs to recombinant resistin resulted in increased expression of the proinflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, through activation of nuclear factor (NF)-kappaB. Resistin induced a rapid increase in intracellular calcium concentration, mainly through calcium release from intracellular inositol triphosphate-sensitive pools. The intracellular calcium chelator BAPTA-AM blocked resistin-induced NF-kappaB activation and monocyte chemoattractant protein-1 expression. In conclusion, this study shows a role for resistin as an intrahepatic cytokine exerting proinflammatory actions in HSCs, via a Ca2+/NF-kappaB-dependent pathway and suggests involvement of this adipokine in the pathophysiology of liver fibrosis.
authors.affiliation: Dipartimento di Medicina Interna, University of Florence, Viale Morgagni, 85, I-50134 Florence, Italy, and the Liver Unit, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Bertolani
authors.forename: Pau
authors.initials: P
authors.lastname: Sancho-Bru
authors.forename: Paola
authors.initials: P
authors.lastname: Failli
authors.forename: Ramon
authors.initials: R
authors.lastname: Bataller
authors.forename: Sara
authors.initials: S
authors.lastname: Aleffi
authors.forename: Raffaella
authors.initials: R
authors.lastname: DeFranco
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mazzinghi
authors.forename: Paola
authors.initials: P
authors.lastname: Romagnani
authors.forename: Stefano
authors.initials: S
authors.lastname: Milani
authors.forename: Pere
authors.initials: P
authors.lastname: Ginés
authors.forename: Jordi
authors.initials: J
authors.lastname: Colmenero
authors.forename: Maurizio
authors.initials: M
authors.lastname: Parola
authors.forename: Stefania
authors.initials: S
authors.lastname: Gelmini
authors.forename: Roberto
authors.initials: R
authors.lastname: Tarquini
authors.forename: Giacomo
authors.initials: G
authors.lastname: Laffi
authors.forename: Massimo
authors.initials: M
authors.lastname: Pinzani
authors.forename: Fabio
authors.initials: F
authors.lastname: Marra
mesh_terms: D000208:Acute Disease; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D006519:Hepatitis, Alcoholic / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D052243:Resistin / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D018925:Chemokines; D016328:NF-kappa B; D052243:Resistin; D002118:Calcium