Inhibition of PU.1 ameliorates metabolic dysfunction and non-alcoholic steatohepatitis.

Journal of Hepatology
Qiongming LiuLi Qiang

Abstract

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...Continue Reading

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Citations

Oct 21, 2020·Cellular & Molecular Immunology·Laura StraussAntonio Sica
Feb 20, 2021·Frontiers in Pharmacology·Qin-Juan SunLan Zhong
Apr 29, 2021·Antioxidants & Redox Signaling·Xiaocheng Charlie DongHyeong Geug Kim
Jun 2, 2021·Journal of Leukocyte Biology·Dongdong MengGuijun Qin

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