Hepatic progenitor cells activation, fibrosis, and adipokines production in pediatric nonalcoholic fatty liver disease

Valerio Nobili, Guido Carpino, Anna Alisi, Antonio Franchitto, Gianfranco Alpini, Rita De Vito, Paolo Onori, Domenico Alvaro, Eugenio Gaudio

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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.

Original languageEnglish
Pages (from-to)2142-2153
Number of pages12
JournalHepatology
Volume56
Issue number6
DOIs
Publication statusPublished - Dec 2012

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Adipokines
Hepatocytes
Fibrosis
Stem Cells
Pediatrics
Glucagon-Like Peptide 1
Resistin
Liver
Adiponectin
Non-alcoholic Fatty Liver Disease
Liver Regeneration
Cell Cycle Checkpoints

ASJC Scopus subject areas

  • Hepatology

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Hepatic progenitor cells activation, fibrosis, and adipokines production in pediatric nonalcoholic fatty liver disease. / Nobili, Valerio; Carpino, Guido; Alisi, Anna; Franchitto, Antonio; Alpini, Gianfranco; De Vito, Rita; Onori, Paolo; Alvaro, Domenico; Gaudio, Eugenio.

In: Hepatology, Vol. 56, No. 6, 12.2012, p. 2142-2153.

Research output: Contribution to journalArticle

Nobili, Valerio ; Carpino, Guido ; Alisi, Anna ; Franchitto, Antonio ; Alpini, Gianfranco ; De Vito, Rita ; Onori, Paolo ; Alvaro, Domenico ; Gaudio, Eugenio. / Hepatic progenitor cells activation, fibrosis, and adipokines production in pediatric nonalcoholic fatty liver disease. In: Hepatology. 2012 ; Vol. 56, No. 6. pp. 2142-2153.
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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.",
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AU - Nobili, Valerio

AU - Carpino, Guido

AU - Alisi, Anna

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AU - Alpini, Gianfranco

AU - De Vito, Rita

AU - Onori, Paolo

AU - Alvaro, Domenico

AU - Gaudio, Eugenio

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