TY - JOUR
T1 - Inhibition of PU.1 ameliorates metabolic dysfunction and non-alcoholic steatohepatitis
AU - Liu, Qiongming
AU - Yu, Junjie
AU - Wang, Liheng
AU - Tang, Yuliang
AU - Zhou, Quan
AU - Ji, Shuhui
AU - Wang, Yi
AU - Santos, Luis
AU - Haeusler, Rebecca A.
AU - Que, Jianwen
AU - Rajbhandari, Prashant
AU - Lei, Xiaoguang
AU - Valenti, Luca
AU - Pajvani, Utpal B.
AU - Qin, Jun
AU - Qiang, Li
N1 - Funding Information:
This work was supported by startup packages of Columbia University (L. Q. and U. B. P.) and Russel Foundation Berrie Foundation (L. Q.), and the myFIRST AIRC grant no. 16888 for the EPIDEMIC-NAFLD project, Ricerca Finalizzata 2016 Ministero della Salute - RF-2016-02364358 (L.V.).
Publisher Copyright:
© 2020 European Association for the Study of the Liver
PY - 2020/8
Y1 - 2020/8
N2 - 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.
AB - 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.
KW - Diabetes
KW - Inflammation
KW - Insulin resistance
KW - Liver
KW - Macrophage
KW - Metabolic dysfunctions
KW - NASH
KW - Obesity
KW - PU.1
UR - http://www.scopus.com/inward/record.url?scp=85084393552&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2020.02.025
DO - 10.1016/j.jhep.2020.02.025
M3 - Article
C2 - 32135178
AN - SCOPUS:85084393552
SN - 0168-8278
VL - 73
SP - 361
EP - 370
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 2
ER -