Inhibition of PU.1 ameliorates metabolic dysfunction and non-alcoholic steatohepatitis.
Animals
Diabetes Mellitus, Type 2
/ drug therapy
Diet, High-Fat
Hepatocytes
/ metabolism
Humans
Liver
/ pathology
Mice
Mice, Knockout
Mice, Obese
/ metabolism
Molecular Targeted Therapy
Non-alcoholic Fatty Liver Disease
/ drug therapy
Obesity
/ drug therapy
Proto-Oncogene Proteins
/ antagonists & inhibitors
RNA, Small Interfering
/ metabolism
Trans-Activators
/ antagonists & inhibitors
Transcription Factors
/ antagonists & inhibitors
Up-Regulation
Diabetes
Inflammation
Insulin resistance
Liver
Macrophage
Metabolic dysfunctions
NASH
Obesity
PU.1
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
19
09
2019
revised:
14
02
2020
accepted:
17
02
2020
pubmed:
7
3
2020
medline:
4
11
2021
entrez:
6
3
2020
Statut:
ppublish
Résumé
Obesity is a well-established risk factor for type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH), but the underlying mechanisms remain incompletely understood. Herein, we aimed to identify novel pathogenic factors (and possible therapeutic targets) underlying metabolic dysfunction in the liver. We applied a tandem quantitative proteomics strategy to enrich and identify transcription factors (TFs) induced in the obese liver. We used flow cytometry of liver cells to analyze the source of the induced TFs. We employed conditional knockout mice, shRNA, and small-molecule inhibitors to test the metabolic consequences of the induction of identified TFs. Finally, we validated mouse data in patient liver biopsies. We identified PU.1/SPI1, the master hematopoietic regulator, as one of the most upregulated TFs in livers from diet-induced obese (DIO) and genetically obese (db/db) mice. Targeting PU.1 in the whole liver, but not hepatocytes alone, significantly improved glucose homeostasis and suppressed liver inflammation. Consistently, treatment with the PU.1 inhibitor DB1976 markedly reduced inflammation and improved glucose homeostasis and dyslipidemia in DIO mice, and strongly suppressed glucose intolerance, liver steatosis, inflammation, and fibrosis in a dietary NASH mouse model. Furthermore, hepatic PU.1 expression was positively correlated with insulin resistance and inflammation in liver biopsies from patients. These data suggest that the elevated hematopoietic factor PU.1 promotes liver metabolic dysfunction, and may be a useful therapeutic target for obesity, insulin resistance/T2D, and NASH. Expression of the immune regulator PU.1 is increased in livers of obese mice and people. Blocking PU.1 improved glucose homeostasis, and reduced liver steatosis, inflammation and fibrosis in mouse models of non-alcoholic steatohepatitis. Inhibition of PU.1 is thus a potential therapeutic strategy for treating obesity-associated liver dysfunction and metabolic diseases.
Sections du résumé
BACKGROUND & AIMS
Obesity is a well-established risk factor for type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH), but the underlying mechanisms remain incompletely understood. Herein, we aimed to identify novel pathogenic factors (and possible therapeutic targets) underlying metabolic dysfunction in the liver.
METHODS
We applied a tandem quantitative proteomics strategy to enrich and identify transcription factors (TFs) induced in the obese liver. We used flow cytometry of liver cells to analyze the source of the induced TFs. We employed conditional knockout mice, shRNA, and small-molecule inhibitors to test the metabolic consequences of the induction of identified TFs. Finally, we validated mouse data in patient liver biopsies.
RESULTS
We identified PU.1/SPI1, the master hematopoietic regulator, as one of the most upregulated TFs in livers from diet-induced obese (DIO) and genetically obese (db/db) mice. Targeting PU.1 in the whole liver, but not hepatocytes alone, significantly improved glucose homeostasis and suppressed liver inflammation. Consistently, treatment with the PU.1 inhibitor DB1976 markedly reduced inflammation and improved glucose homeostasis and dyslipidemia in DIO mice, and strongly suppressed glucose intolerance, liver steatosis, inflammation, and fibrosis in a dietary NASH mouse model. Furthermore, hepatic PU.1 expression was positively correlated with insulin resistance and inflammation in liver biopsies from patients.
CONCLUSIONS
These data suggest that the elevated hematopoietic factor PU.1 promotes liver metabolic dysfunction, and may be a useful therapeutic target for obesity, insulin resistance/T2D, and NASH.
LAY SUMMARY
Expression of the immune regulator PU.1 is increased in livers of obese mice and people. Blocking PU.1 improved glucose homeostasis, and reduced liver steatosis, inflammation and fibrosis in mouse models of non-alcoholic steatohepatitis. Inhibition of PU.1 is thus a potential therapeutic strategy for treating obesity-associated liver dysfunction and metabolic diseases.
Identifiants
pubmed: 32135178
pii: S0168-8278(20)30124-0
doi: 10.1016/j.jhep.2020.02.025
pii:
doi:
Substances chimiques
Proto-Oncogene Proteins
0
RNA, Small Interfering
0
Trans-Activators
0
Transcription Factors
0
proto-oncogene protein Spi-1
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
361-370Informations de copyright
Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.