A Recent study led by Dr. XIE Dong’s group from Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences, reveals the role and mechanism of pancreatic progenitor cell differentiation and proliferation factor (PPDPF)  in hepatic steatosis, providing therapeutic targets for treatment of Non-alcoholic fatty liver disease (NAFLD).  

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, the researchers found 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 High fat diet (HFD). Mechanistic study revealed that PPDPF negatively regulates mTORC1-S6K-SREBP1 signaling. PPDPF interfered with the interaction between Raptor and DDB1-CUL4, an E3 ligase complex, which prevents ubiquitination and activation of Raptor. Accordingly, liver-specific PPDPF overexpression effectively inhibited HFD-induced mTOR signaling activation and hepatic steatosis in mice.  

Altogether, this work suggested that PPDPF is a novel regulator of mTORC1 signaling in lipid metabolism, and may be a potential therapeutic candidate for NAFLD. 

This work entitled “PPDPF alleviates hepatic steatosis through inhibition of mTOR signaling” was published online in Nature Communications on May 24, 2021. 

The doctoral students MA Ning and WANG Yi-kang are the co-first authors, and Dr. XIE Dong and Dr. LI Jing-Jing are the co-corresponding authors of this publication. The study was funded by the grants from National Key R&D Program of China, National Natural Science Foundation of China, Youth Innovation Promotion Association of Chinese Academy of Sciences fund and Sanofi-SIBS 2018 Young Faculty Award. The authors appreciate Professor LI Yu from SINH and Professor DU Jia-mu (Southern University of Science and Technology) for their helpful suggestions on this study and Professor DING Qiu-rong from SINH for the gift of AAV8 constructs.

Schematic diagram of PPDPF working mode. (Image by Dr. XIE Dong's group) 

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Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
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