Periostin antisense oligonucleotide prevents hepatic steatosis and fibrosis in a mouse model of non-alcoholic steatohepatitis.
Animals
Cell Adhesion Molecules
/ genetics
Cell Line
Disease Models, Animal
Down-Regulation
/ drug effects
Fibrosis
/ prevention & control
Gene Expression
/ drug effects
Humans
Liver
/ metabolism
Male
Mice
Mice, Inbred C57BL
Molecular Targeted Therapy
Non-alcoholic Fatty Liver Disease
/ genetics
Oligonucleotides, Antisense
/ pharmacology
PPAR alpha
/ genetics
antisense oligonucleotides
non-alcoholic steatohepatitis
periostin
peroxisome proliferator-activated receptor-alpha
Journal
Journal of gastroenterology and hepatology
ISSN: 1440-1746
Titre abrégé: J Gastroenterol Hepatol
Pays: Australia
ID NLM: 8607909
Informations de publication
Date de publication:
Dec 2020
Dec 2020
Historique:
received:
27
02
2020
revised:
14
04
2020
accepted:
28
04
2020
pubmed:
5
5
2020
medline:
31
7
2021
entrez:
5
5
2020
Statut:
ppublish
Résumé
Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, inflammation, and hepatocellular injury with varying degrees of fibrosis. There are currently no established treatment approaches for NASH other than lifestyle interventions. Periostin, a matricellular protein required for tissue remodeling and fibrosis, plays an important role in hepatic steatosis and fibrosis and could be a potential target for NASH treatment. Advances in molecular biology and biochemical engineering have led to the development of antisense oligonucleotides (ASOs) that can inhibit target genes with no significant toxic effects. Herein, we investigated the therapeutic effects of periostin-targeting ASO (PNASO) in NASH. C57BL/6J mice were fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) to induce NASH with or without intraperitoneal injection of mouse PNASO. To explore the role of periostin in hepatocellular steatosis, Hc3716 cells, an immortalized human hepatocyte line, were treated with recombinant periostin in vitro. The induced periostin expression in the liver of CDAHFD-fed mice was significantly suppressed by PNASO. The deletion of hepatic periostin by PNASO significantly ameliorated hepatic steatosis while restoring the expression levels of peroxisome proliferator-activated receptor-alpha (PPAR-α) and its target genes. PNASO also inhibited hepatic fibrosis, reflected by the reduction of alpha-smooth muscle actin, collagen type I, and other fibrotic markers. In vitro experiments demonstrated that treatment with recombinant periostin increased cellular lipid accumulation in Hc3716 cells accompanied with the downregulation of PPAR-α. Periostin-targeting ASO is a potential therapeutic approach for the efficient treatment of hepatic steatosis and fibrosis in NASH.
Sections du résumé
BACKGROUND AND AIM
OBJECTIVE
Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, inflammation, and hepatocellular injury with varying degrees of fibrosis. There are currently no established treatment approaches for NASH other than lifestyle interventions. Periostin, a matricellular protein required for tissue remodeling and fibrosis, plays an important role in hepatic steatosis and fibrosis and could be a potential target for NASH treatment. Advances in molecular biology and biochemical engineering have led to the development of antisense oligonucleotides (ASOs) that can inhibit target genes with no significant toxic effects. Herein, we investigated the therapeutic effects of periostin-targeting ASO (PNASO) in NASH.
METHODS
METHODS
C57BL/6J mice were fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) to induce NASH with or without intraperitoneal injection of mouse PNASO. To explore the role of periostin in hepatocellular steatosis, Hc3716 cells, an immortalized human hepatocyte line, were treated with recombinant periostin in vitro.
RESULTS
RESULTS
The induced periostin expression in the liver of CDAHFD-fed mice was significantly suppressed by PNASO. The deletion of hepatic periostin by PNASO significantly ameliorated hepatic steatosis while restoring the expression levels of peroxisome proliferator-activated receptor-alpha (PPAR-α) and its target genes. PNASO also inhibited hepatic fibrosis, reflected by the reduction of alpha-smooth muscle actin, collagen type I, and other fibrotic markers. In vitro experiments demonstrated that treatment with recombinant periostin increased cellular lipid accumulation in Hc3716 cells accompanied with the downregulation of PPAR-α.
CONCLUSIONS
CONCLUSIONS
Periostin-targeting ASO is a potential therapeutic approach for the efficient treatment of hepatic steatosis and fibrosis in NASH.
Substances chimiques
Cell Adhesion Molecules
0
Oligonucleotides, Antisense
0
POSTN protein, human
0
PPAR alpha
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2140-2150Subventions
Organisme : JSPS Grant-in-Aid for Young Scientists
ID : 19K18963
Organisme : JSPS Grant-in-Aid for Young Scientists (B)
ID : 17K15620
Organisme : for Young Scientists
ID : 19K18963
Organisme : for Young Scientists (B)
ID : 17K15620
Organisme : JSPS Grant-in-Aid for Scientific Research (C)
ID : 18K07940
Organisme : for Young Scientists
Organisme : for Young Scientists (B)
Informations de copyright
© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.
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