Alleviation of Hepatic Steatosis by 4‐azidophlorizin via the Degradation of Geranylgeranyl Diphosphate Synthase by the Ubiquitin‐Proteasome Pathway in Vivo and in Vitro

Author:

Ye Juan12,Qi Yaling3,Chen Jiao2,Zhang Shihu4,Liu Boyuan5,Zhao Yinjuan6,Yuan Xianwen7,Cheng Qi1,Yang Yang2,Zhang Furong5,Gao Hongliang5,Wang Haoran8,Wu Jing5,Zhu Feng9,Li Chaojun10,Cao Peng2,Xue Bin5ORCID

Affiliation:

1. Medical School Nanjing University Nanjing Jiangsu 210023 China

2. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine Nanjing University of Chinese Medicine Nanjing Jiangsu 210028 China

3. Department of Histology and Embryology State Key Laboratory of Reproductive Medicine Nanjing Medical University Nanjing 211166 China

4. Department of General Surgery Affiliated Hospital of Nanjing University of Chinese Medicine Nanjing 210029 China

5. Core Laboratory Sir Run Run Hospital Nanjing Medical University Nanjing Jiangsu 211166 China

6. Collaborative Innovation Center of Sustainable Forestry in Southern China College of Forestry Nanjing Forestry University Nanjing 210037 China

7. Department of Hepatobiliary Surgery The Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing 210023 China

8. School of Pharmacy Nanjing University of Chinese Medicine Nanjing 210000 China

9. General surgery department Sir Run Run Hospital Nanjing Medical University Nanjing 211166 China

10. State Key Laboratory of Reproductive Medicine and China International Joint Research Center on Environment and Human Health Center for Global Health School of Public Health Nanjing Medical University Nanjing 211166 China

Abstract

AbstractThere are no known approved pharmacotherapies for non‐alcoholic fatty liver disease (NAFLD) in the clinical setting. Although studies have provided substantial evidence that geranylgeranyl diphosphate synthase (GGPPS) is a potential therapeutic target for the treatment of NAFLD corresponding drug screening is rare. A GGPPS‐targeted inhibitor is identified using a structure‐based virtual small molecule screening method. The interaction of 4‐AZ and GGPPS is detected by microscale thermophoresis. 4‐AZ degradation of GGPPS by the ubiquitin‐proteasome pathway is detected by western blotting. The anti‐steatotic effect of 4‐AZ in vivo is detected by CT. Lipid‐related gene detection is detected by real‐time PCR both in primary hepatocytes and mice. The compound inhibits the accumulation of lipids in primary hepatocytes and decreases lipogenic gene expression through GGPPS. Pharmacological studies show that 4‐AZ can attenuate hepatic steatosis and improve liver injury in high‐fat diet‐induced mice. This data provides a novel application of 4‐AZ NAFLD therapy, proving that the inhibition of GGPPS is a novel strategy for the treatment of NAFLD.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

General Medicine

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