| Title | Inhibition of PU.1 ameliorates metabolic dysfunction and non-alcoholic steatohepatitis |
| Authors | Liu, Qiongming Yu, Junjie Wang, Liheng Tang, Yuliang Zhou, Quan Ji, Shuhui Wang, Yi Santos, Luis Haeusler, Rebecca A. Que, Jianwen Rajbhandari, Prashant Lei, Xiaoguang Valenti, Luca Pajvani, Utpal B. Qin, Jun Qiang, Li |
| Affiliation | Columbia Univ, Coll Phys & Surg, Naomi Berrie Diabet Ctr, Dept Pathol & Cell Biol, New York, NY 10032 USA Natl Ctr Prot Sci, Beijing Proteome Res Ctr, Beijing Inst Life, State Key Lab Prote,PHOENIX Ctr Beijing, Beijing 102206, Peoples R China Columbia Univ, Coll Phys & Surg, Naomi Berrie Diabet Ctr, Dept Med, New York, NY 10032 USA Peking Univ, Coll Chem & Mol Engn,Beijing Natl Lab Mol Sci, Synthet & Funct Biomol Ctr,Key Lab Bioorgan Chem, Peking Tsinghua Ctr Life Sci,Minist Educ,Dept Che, Beijing 100871, Peoples R China Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA Icahn Sch Med Mt Sinai, Diabet Obes & Metab Inst, New York, NY 10029 USA Columbia Univ, Columbia Ctr Human Dev, New York, NY 10032 USA Columbia Univ, Dept Med, New York, NY 10032 USA Univ Milan, Dept Pathophysiol & Transplantat, Milan, Italy Fdn IRCCS Ca Granda Osped Policlin, Internal Med & Metab Dis, Milan, Italy |
| Keywords | TRANSCRIPTION FACTOR PU.1 FATTY LIVER-DISEASE TYPE-2 DIABETES-MELLITUS INSULIN-RESISTANCE MACROPHAGE POLARIZATION ALTERNATIVE ACTIVATION HEPATIC MACROPHAGES KUPFFER CELLS OBESITY EXPRESSION |
| Issue Date | Aug-2020 |
| Publisher | JOURNAL OF HEPATOLOGY |
| Abstract | 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. (c) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. |
| URI | http://hdl.handle.net/20.500.11897/617358 |
| ISSN | 0168-8278 |
| DOI | 10.1016/j.jhep.2020.02.025 |
| Indexed | SCI(E) |
| Appears in Collections: | å å¦ä¸ å å å·¥ç¨ å¦é ¢ 生物有机与分子工程教育部重点实验室 |
