Nonalcoholic Steatohepatitis and HCC in a Hyperphagic Mouse Accelerated by Western Diet.
Animals
Biomarkers
Carcinoma, Hepatocellular
/ etiology
Cell Cycle Proteins
/ deficiency
Diet, Western
/ adverse effects
Disease Models, Animal
Disease Susceptibility
Dyslipidemias
/ complications
Gene Expression Profiling
Hyperphagia
/ complications
Immunohistochemistry
Insulin Resistance
Liver Cirrhosis
/ complications
Liver Neoplasms
/ etiology
Mice
Mice, Knockout
Non-alcoholic Fatty Liver Disease
/ complications
Obesity
/ complications
Gut Inflammation
Hepatocellular Carcinoma
Liver Inflammation
NASH Regression
Nonalcoholic Steatohepatitis
Journal
Cellular and molecular gastroenterology and hepatology
ISSN: 2352-345X
Titre abrégé: Cell Mol Gastroenterol Hepatol
Pays: United States
ID NLM: 101648302
Informations de publication
Date de publication:
2021
2021
Historique:
received:
20
01
2021
revised:
14
05
2021
accepted:
15
05
2021
pubmed:
2
6
2021
medline:
23
3
2022
entrez:
1
6
2021
Statut:
ppublish
Résumé
How benign liver steatosis progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) remains elusive. NASH progression entails diverse pathogenic mechanisms and relies on complex cross-talk between multiple tissues such as the gut, adipose tissues, liver, and the brain. Using a hyperphagic mouse fed with a Western diet (WD), we aimed to elucidate the cross-talk and kinetics of hepatic and extrahepatic alterations during NASH-HCC progression, as well as regression. Hyperphagic mice lacking a functional Alms1 gene (Foz/Foz) and wild-type littermates were fed WD or standard chow for 12 weeks for NASH/fibrosis and for 24 weeks for HCC development. NASH regression was modeled by switching back to normal chow after NASH development. Foz+WD mice were steatotic within 1 to 2 weeks, developed NASH by 4 weeks, and grade 3 fibrosis by 12 weeks, accompanied by chronic kidney injury. Foz+WD mice that continued on WD progressed to cirrhosis and HCC within 24 weeks and had reduced survival as a result of cardiac dysfunction. However, NASH mice that were switched to normal chow showed NASH regression, improved survival, and did not develop HCC. Transcriptomic and histologic analyses of Foz/Foz NASH liver showed strong concordance with human NASH. NASH was preceded by an early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation. This led to acute-phase liver inflammation in Foz+WD mice, characterized by neutrophil infiltration and increased levels of several chemokines/cytokines. The liver cytokine/chemokine profile evolved as NASH progressed, with subsequent predominance by monocyte recruitment. The Foz+WD model closely mimics the pathobiology and gene signature of human NASH with fibrosis and subsequent HCC. Foz+WD mice provide a robust and relevant preclinical model of NASH, NASH-associated HCC, chronic kidney injury, and heart failure.
Sections du résumé
BACKGROUND & AIMS
How benign liver steatosis progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) remains elusive. NASH progression entails diverse pathogenic mechanisms and relies on complex cross-talk between multiple tissues such as the gut, adipose tissues, liver, and the brain. Using a hyperphagic mouse fed with a Western diet (WD), we aimed to elucidate the cross-talk and kinetics of hepatic and extrahepatic alterations during NASH-HCC progression, as well as regression.
METHODS
Hyperphagic mice lacking a functional Alms1 gene (Foz/Foz) and wild-type littermates were fed WD or standard chow for 12 weeks for NASH/fibrosis and for 24 weeks for HCC development. NASH regression was modeled by switching back to normal chow after NASH development.
RESULTS
Foz+WD mice were steatotic within 1 to 2 weeks, developed NASH by 4 weeks, and grade 3 fibrosis by 12 weeks, accompanied by chronic kidney injury. Foz+WD mice that continued on WD progressed to cirrhosis and HCC within 24 weeks and had reduced survival as a result of cardiac dysfunction. However, NASH mice that were switched to normal chow showed NASH regression, improved survival, and did not develop HCC. Transcriptomic and histologic analyses of Foz/Foz NASH liver showed strong concordance with human NASH. NASH was preceded by an early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation. This led to acute-phase liver inflammation in Foz+WD mice, characterized by neutrophil infiltration and increased levels of several chemokines/cytokines. The liver cytokine/chemokine profile evolved as NASH progressed, with subsequent predominance by monocyte recruitment.
CONCLUSIONS
The Foz+WD model closely mimics the pathobiology and gene signature of human NASH with fibrosis and subsequent HCC. Foz+WD mice provide a robust and relevant preclinical model of NASH, NASH-associated HCC, chronic kidney injury, and heart failure.
Identifiants
pubmed: 34062281
pii: S2352-345X(21)00099-0
doi: 10.1016/j.jcmgh.2021.05.010
pmc: PMC8342972
pii:
doi:
Substances chimiques
Alms1 protein, mouse
0
Biomarkers
0
Cell Cycle Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
891-920Subventions
Organisme : NIAID NIH HHS
ID : R37 AI043477
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK120515
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA029019
Pays : United States
Organisme : NCATS NIH HHS
ID : KL2 TR001444
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA028550
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA022614
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK101737
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK088837
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA018663
Pays : United States
Organisme : NINDS NIH HHS
ID : P30 NS047101
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK111866
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK099205
Pays : United States
Organisme : NIAAA NIH HHS
ID : P50 AA011999
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI043477
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.