Resistin as an intrahepatic cytokine: overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells.
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.
Bertolani
Cristiana
C
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.
Sancho-Bru
Pau
P
Failli
Paola
P
Bataller
Ramon
R
Aleffi
Sara
S
DeFranco
Raffaella
R
Mazzinghi
Benedetta
B
Romagnani
Paola
P
Milani
Stefano
S
Ginés
Pere
P
Colmenero
Jordi
J
Parola
Maurizio
M
Gelmini
Stefania
S
Tarquini
Roberto
R
Laffi
Giacomo
G
Pinzani
Massimo
M
Marra
Fabio
F
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
D018925:Chemokines; D016328:NF-kappa B; D052243:Resistin; D002118:Calcium