title: Hepatic progenitor cells activation, fibrosis, and adipokines production in pediatric nonalcoholic fatty liver disease.
abstract: Hepatic progenitor cells (HPCs) play a major role in liver repair and regeneration. We evaluated HPC involvement in pediatric nonalcoholic fatty liver disease (pNAFLD). Thirty biopsies of consecutive children and adolescents with untreated NAFLD (19 with nonalcoholic steatohepatitis [NASH] and 11 without NASH) were studied using immunohistochemistry and immunofluorescence. HPCs and HPC-expressing adipokines (e.g., adiponectin, resistin, and glucagon-like peptide 1 [GLP-1]) were counted and correlated with steatosis, inflammation, hepatocyte ballooning, fibrosis, and NAFLD activity score (NAS). The HPC compartment was expanded in pNAFLD, especially in children with NASH, and was independently associated with degree of fibrosis (r = 0.303; P = 0.033). NASH livers were also characterized by increased hepatocyte apoptosis, cell-cycle arrest, and an expanded pool of intermediate hepatocytes. Adiponectin expression in HPCs of pNAFLD patients was down-regulated with respect to the healthy liver, and this expression was inversely correlated with NAS score (r = -0.792; P < 0.001) and steatosis (r = -0.769; P < 0.001). Resistin expression in HPCs increased in pNAFLD and was related to degree of fibrosis (r = 0.432; P < 0.05). GLP-1 was overexpressed in HPCs of pNAFLD patients, and GLP-1 expression was related to degree of steatosis (r = 0.577; P < 0.05) and NAS (r = 0.594; P < 0.01).
  
  
  CONCLUSIONS
  HPC activation is involved in the response of the liver to oxidative stress in pNAFLD and is correlated with fibrosis and the progression toward NASH. HPCs express adiponectin, resistin, and GLP-1, which become available to resident liver cells and are strongly associated with the severity of NAFLD. These results may have important pathophysiological implications in the modulation of hepatic insulin resistance and the progression of liver injury.
authors.affiliation: Unit of Liver Research, Bambino Gesù Children's Hospital, Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Nobili
authors.forename: Guido
authors.initials: G
authors.lastname: Carpino
authors.forename: Anna
authors.initials: A
authors.lastname: Alisi
authors.forename: Antonio
authors.initials: A
authors.lastname: Franchitto
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.forename: Rita
authors.initials: R
authors.lastname: De Vito
authors.forename: Paolo
authors.initials: P
authors.lastname: Onori
authors.forename: Domenico
authors.initials: D
authors.lastname: Alvaro
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D000293:Adolescent; D017209:Apoptosis; D002452:Cell Count; D059447:Cell Cycle Checkpoints; D002648:Child; D005234:Fatty Liver / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006505:Hepatitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D052243:Resistin / Q000378:metabolism; D012720:Severity of Illness Index; D013234:Stem Cells / Q000378:metabolism* / Q000502:physiology
chemical_list: D052242:Adiponectin; D052243:Resistin; D052216:Glucagon-Like Peptide 1