Inhibition of PU.1 ameliorates metabolic dysfunction and non-alcoholic steatohepatitis
| Autor: | Jianwen Que, Prashant Rajbhandari, Utpal B. Pajvani, Li Qiang, Jun Qin, Qiongming Liu, Liheng Wang, Shuhui Ji, Luca Valenti, Yuliang Tang, Rebecca A. Haeusler, Quan Zhou, Junjie Yu, Xiaoguang Lei, Luis C. Santos, Yi Wang |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Mice Obese Inflammation Type 2 diabetes Diet High-Fat Mice 03 medical and health sciences 0302 clinical medicine Insulin resistance Downregulation and upregulation Non-alcoholic Fatty Liver Disease Fibrosis Proto-Oncogene Proteins Internal medicine Diabetes mellitus medicine Animals Humans Glucose homeostasis Molecular Targeted Therapy Obesity RNA Small Interfering Mice Knockout Hepatology business.industry medicine.disease Up-Regulation 030104 developmental biology Endocrinology Diabetes Mellitus Type 2 Liver Hepatocytes Trans-Activators 030211 gastroenterology & hepatology medicine.symptom Steatohepatitis business Transcription Factors |
| Zdroj: | Journal of Hepatology. 73:361-370 |
| ISSN: | 0168-8278 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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