Metabolic regulation of hepatic PNPLA3 expression and severity of liver fibrosis in patients with NASH.
genetic polymorphism
lipase
lipid stress
non-alcoholic fatty liver disease
Journal
Liver international : official journal of the International Association for the Study of the Liver
ISSN: 1478-3231
Titre abrégé: Liver Int
Pays: United States
ID NLM: 101160857
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
23
09
2019
revised:
31
01
2020
accepted:
03
02
2020
pubmed:
12
2
2020
medline:
22
6
2021
entrez:
12
2
2020
Statut:
ppublish
Résumé
The genetic PNPLA3 polymorphism I148M has been extensively associated with higher risk for development and progression of NAFLD towards NASH. PNPLA3 and α-SMA expression were quantified in liver biopsies collected from NASH patients (n = 26) with different fibrosis stages and PNPLA3 genotypes. To study the potential mechanisms driving PNPLA3 expression during NASH progression towards fibrosis, hepatocytes and hepatic stellate cells (HSCs) were cultivated in low and high glucose medium. Moreover, hepatocytes were treated with increasing concentrations of palmitic acid alone or in combination with glucose. Conditioned media were collected from challenged hepatocytes to stimulate HSCs. Tissue expression of PNPLA3 was significantly enhanced in biopsies of patients carrying the I148M polymorphism compared to wild type (WT). In NASH biopsies, PNPLA3 significantly correlated with fibrosis stage and α-SMA levels independently of PNPLA3 genotype. In line, PNPLA3 expression was higher in α-SMA positive cells. Low glucose increased PNPLA3 in HSCs, whereas high glucose induced PNPLA3 and de-novo lipogenesis-related genes expression in hepatocytes. Palmitic acid induced fat accumulation and cell stress markers in hepatocytes, which could be counteracted by oleic acid. Conditioned media collected from lipotoxic challenged hepatocytes markedly induced PNPLA3 mRNA and protein levels, fibrogenic and autophagic markers and promoted migration in HSCs. Notably, conditioned media collected from hepatocytes cultivated with both glucose and palmitic acid exacerbated HSCs migration, PNPLA3 and fibrogenic gene expression, promoting release of cytokines from HSCs. Collectively, our observations uncover the diverse metabolic regulation of PNPLA3 among different hepatic cell populations and support its relation to fibrosis progression.
Sections du résumé
BACKGROUND AND AIMS
The genetic PNPLA3 polymorphism I148M has been extensively associated with higher risk for development and progression of NAFLD towards NASH.
METHODS
PNPLA3 and α-SMA expression were quantified in liver biopsies collected from NASH patients (n = 26) with different fibrosis stages and PNPLA3 genotypes. To study the potential mechanisms driving PNPLA3 expression during NASH progression towards fibrosis, hepatocytes and hepatic stellate cells (HSCs) were cultivated in low and high glucose medium. Moreover, hepatocytes were treated with increasing concentrations of palmitic acid alone or in combination with glucose. Conditioned media were collected from challenged hepatocytes to stimulate HSCs.
RESULTS
Tissue expression of PNPLA3 was significantly enhanced in biopsies of patients carrying the I148M polymorphism compared to wild type (WT). In NASH biopsies, PNPLA3 significantly correlated with fibrosis stage and α-SMA levels independently of PNPLA3 genotype. In line, PNPLA3 expression was higher in α-SMA positive cells. Low glucose increased PNPLA3 in HSCs, whereas high glucose induced PNPLA3 and de-novo lipogenesis-related genes expression in hepatocytes. Palmitic acid induced fat accumulation and cell stress markers in hepatocytes, which could be counteracted by oleic acid. Conditioned media collected from lipotoxic challenged hepatocytes markedly induced PNPLA3 mRNA and protein levels, fibrogenic and autophagic markers and promoted migration in HSCs. Notably, conditioned media collected from hepatocytes cultivated with both glucose and palmitic acid exacerbated HSCs migration, PNPLA3 and fibrogenic gene expression, promoting release of cytokines from HSCs.
CONCLUSIONS
Collectively, our observations uncover the diverse metabolic regulation of PNPLA3 among different hepatic cell populations and support its relation to fibrosis progression.
Identifiants
pubmed: 32043752
doi: 10.1111/liv.14402
pmc: PMC7318357
doi:
Substances chimiques
Membrane Proteins
0
Lipase
EC 3.1.1.3
adiponutrin, human
EC 3.1.1.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1098-1110Informations de copyright
© 2020 The Authors. Liver International published by John Wiley & Sons Ltd.
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