PPDPF alleviates hepatic steatosis through inhibition of mTOR signaling

Ning Ma, Yi-Kang Wang, Sheng Xu, Qian-Zhi Ni, Qian-Wen Zheng, Bing Zhu, Hui-Jun Cao, Hao Jiang, Feng-Kun Zhang, Yan-Mei Yuan, Er-Bin Zhang, Tian-Wei Chen, Ji Xia, Xu-Fen Ding, Zhen-Hua Chen, Xiu-Ping Zhang, Kang Wang, Shu-Qun Cheng, Lin Qiu, Zhi-Gang Li, Yong-Chun Yu, Xiao-Fan Wang, Bin Zhou, Jing-Jing Li () and Dong Xie ()
Additional contact information
Ning Ma: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yi-Kang Wang: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Sheng Xu: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Qian-Zhi Ni: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Qian-Wen Zheng: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Bing Zhu: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Hui-Jun Cao: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Hao Jiang: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Feng-Kun Zhang: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yan-Mei Yuan: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Er-Bin Zhang: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Tian-Wei Chen: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Ji Xia: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Xu-Fen Ding: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Zhen-Hua Chen: Second Military Medical University
Xiu-Ping Zhang: The First Medical Center of Chinese People’s Liberation Army (PLA) General Hospital
Kang Wang: Second Military Medical University
Shu-Qun Cheng: Second Military Medical University
Lin Qiu: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Zhi-Gang Li: Shanghai Jiao Tong University
Yong-Chun Yu: Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University
Xiao-Fan Wang: Duke University Medical Center
Bin Zhou: Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences
Jing-Jing Li: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Dong Xie: Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in the world, however, no drug treatment has been approved for this disease. Thus, it is urgent to find effective therapeutic targets for clinical intervention. In this study, we find that liver-specific knockout of PPDPF (PPDPF-LKO) leads to spontaneous fatty liver formation in a mouse model at 32 weeks of age on chow diets, which is enhanced by HFD. Mechanistic study reveals that PPDPF negatively regulates mTORC1-S6K-SREBP1 signaling. PPDPF interferes with the interaction between Raptor and CUL4B-DDB1, an E3 ligase complex, which prevents ubiquitination and activation of Raptor. Accordingly, liver-specific PPDPF overexpression effectively inhibits HFD-induced mTOR signaling activation and hepatic steatosis in mice. These results suggest that PPDPF is a regulator of mTORC1 signaling in lipid metabolism, and may be a potential therapeutic candidate for NAFLD.

Date: 2021
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DOI: 10.1038/s41467-021-23285-8

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