PPDPF alleviates hepatic steatosis through inhibition of mTOR signaling

Ning Ma,Feng-Kun Zhang,Kang Wang,Xue Ding ,Er‐Bin Zhang ,Xiuping Zhang ,Hui‐Jun Cao ,Jingjing Li ,Shuqun Cheng ,Yikang Wang ,Zhenhua Chen ,Zhigang Li ,Qian‐Zhi Ni ,Qian‐Wen Zheng ,Tianwei Chen ,Xiaofan Wang ,Yongchun Yu ,Yang Yuan ,Bin Zhou,Hao Jiang,Sheng Xu,Ji Xia,Bing Zhu,Lin Qiu,Dong Xie

doi:10.1038/s41467-021-23285-8

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.

Highlights

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in the world, no drug treatment has been approved for this disease
Serum triglycerides (TG) (Supplementary Fig. 1c) and liver TG, NEFA (Fig. 1e, f) were dramatically increased in Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) LKO group. qPCR analysis of liver tissues revealed that mRNA levels of the key molecules in fatty acid synthesis were higher in PPDPF-LKO mice, including SREBP1, FASN, ACLY, ME, and PPARG (Fig. 1g)
These data suggested that PPDPF-LKO mice were more susceptible to fatty liver disease

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease in the world, no drug treatment has been approved for this disease. 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. 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. PPDPF overexpression via vein injection of AAV8-PPDPF effectively suppresses HFD-induced mTOR signaling activation and fatty liver. Our study identifies PPDPF as a negative regulator of lipogenesis by inhibiting mTOR-S6K-SREBP1 signaling and provides a promising therapeutic candidate for NAFLD

Methods

Results

Conclusion