PPDPF Alleviates Hepatic Steatosis Through Inhibition of MTOR Signaling

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 25

PMID 34031390

Citations 18

Authors

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

Dong Xie

Affiliations

Soon will be listed here.

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.

Citing Articles

Trans-ancestral rare variant association study with machine learning-based phenotyping for metabolic dysfunction-associated steatotic liver disease.

Chen R, Petrazzini B, Duffy A, Rocheleau G, Jordan D, Bansal M Genome Biol. 2025; 26(1):50.

PMID: 40065360 PMC: 11892324. DOI: 10.1186/s13059-025-03518-5.

PPDPF-mediated regulation of BCAA metabolism enhances mTORC1 activity and drives cholangiocarcinoma progression.

Li Z, Guan Y, Gao J, Zhu L, Zeng Z, Jing Q Oncogene. 2025; .

PMID: 40025229 DOI: 10.1038/s41388-025-03320-4.

Ubiquitination and Metabolic Disease.

Ma M, Cao R, Tian Y, Fu X Adv Exp Med Biol. 2024; 1466:47-79.

PMID: 39546135 DOI: 10.1007/978-981-97-7288-9_4.

Mechanism of Metabolic Dysfunction-associated Steatotic Liver Disease: Important role of lipid metabolism.

Feng X, Zhang R, Yang Z, Zhang K, Xing J J Clin Transl Hepatol. 2024; 12(9):815-826.

PMID: 39280069 PMC: 11393839. DOI: 10.14218/JCTH.2024.00019.

Exercise, mTOR Activation, and Potential Impacts on the Liver in Rodents.

Onaka G, Carvalho M, Onaka P, Barbosa C, Martinez P, de Oliveira-Junior S Biology (Basel). 2024; 13(6).

PMID: 38927242 PMC: 11201249. DOI: 10.3390/biology13060362.

References

Wang Y, Viscarra J, Kim S, Sul H . Transcriptional regulation of hepatic lipogenesis. Nat Rev Mol Cell Biol. 2015; 16(11):678-89. PMC: 4884795. DOI: 10.1038/nrm4074. View

Steen V, Skrede S, Polushina T, Lopez M, Andreassen O, Ferno J . Genetic evidence for a role of the SREBP transcription system and lipid biosynthesis in schizophrenia and antipsychotic treatment. Eur Neuropsychopharmacol. 2016; 27(6):589-598. DOI: 10.1016/j.euroneuro.2016.07.011. View

Anstee Q, Reeves H, Kotsiliti E, Govaere O, Heikenwalder M . From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol. 2019; 16(7):411-428. DOI: 10.1038/s41575-019-0145-7. View

Kim J, Guan K . mTOR as a central hub of nutrient signalling and cell growth. Nat Cell Biol. 2019; 21(1):63-71. DOI: 10.1038/s41556-018-0205-1. View

Ghosh P, Wu M, Zhang H, Sun H . mTORC1 signaling requires proteasomal function and the involvement of CUL4-DDB1 ubiquitin E3 ligase. Cell Cycle. 2008; 7(3):373-81. DOI: 10.4161/cc.7.3.5267. View

Lewis C, Griffiths B, Santos C, Pende M, Schulze A . Regulation of the SREBP transcription factors by mTORC1. Biochem Soc Trans. 2011; 39(2):495-9. DOI: 10.1042/BST0390495. View

Iovine B, Iannella M, Bevilacqua M . Damage-specific DNA binding protein 1 (DDB1): a protein with a wide range of functions. Int J Biochem Cell Biol. 2011; 43(12):1664-7. DOI: 10.1016/j.biocel.2011.09.001. View

Alkhouri N, Scott A . An Update on the Pharmacological Treatment of Nonalcoholic Fatty Liver Disease: Beyond Lifestyle Modifications. Clin Liver Dis (Hoboken). 2019; 11(4):82-86. PMC: 6370316. DOI: 10.1002/cld.708. View

Saxton R, Sabatini D . mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017; 168(6):960-976. PMC: 5394987. DOI: 10.1016/j.cell.2017.02.004. View

10.

Engelking L, Cantoria M, Xu Y, Liang G . Developmental and extrahepatic physiological functions of SREBP pathway genes in mice. Semin Cell Dev Biol. 2017; 81:98-109. PMC: 5775927. DOI: 10.1016/j.semcdb.2017.07.011. View

11.

Han J, Wang Y . mTORC1 signaling in hepatic lipid metabolism. Protein Cell. 2017; 9(2):145-151. PMC: 5818363. DOI: 10.1007/s13238-017-0409-3. View

12.

Friedman S, Neuschwander-Tetri B, Rinella M, Sanyal A . Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018; 24(7):908-922. PMC: 6553468. DOI: 10.1038/s41591-018-0104-9. View

13.

Bakan I, Laplante M . Connecting mTORC1 signaling to SREBP-1 activation. Curr Opin Lipidol. 2012; 23(3):226-234. DOI: 10.1097/MOL.0b013e328352dd03. View

14.

Hussain S, Feldman A, Das C, Ziesmer S, Ansell S, Galardy P . Ubiquitin hydrolase UCH-L1 destabilizes mTOR complex 1 by antagonizing DDB1-CUL4-mediated ubiquitination of raptor. Mol Cell Biol. 2013; 33(6):1188-97. PMC: 3592026. DOI: 10.1128/MCB.01389-12. View

15.

Softic S, Cohen D, Kahn C . Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease. Dig Dis Sci. 2016; 61(5):1282-93. PMC: 4838515. DOI: 10.1007/s10620-016-4054-0. View

16.

Laplante M, Sabatini D . mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93. PMC: 3331679. DOI: 10.1016/j.cell.2012.03.017. View

17.

Younossi Z . Non-alcoholic fatty liver disease - A global public health perspective. J Hepatol. 2018; 70(3):531-544. DOI: 10.1016/j.jhep.2018.10.033. View

18.

Rinella M, Sanyal A . Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol. 2016; 13(4):196-205. DOI: 10.1038/nrgastro.2016.3. View

19.

Drescher H, Weiskirchen S, Weiskirchen R . Current Status in Testing for Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH). Cells. 2019; 8(8). PMC: 6721710. DOI: 10.3390/cells8080845. View

20.

Shi S, Deng Y, Zhao J, Ji X, Shi J, Feng Y . RACK1 promotes non-small-cell lung cancer tumorigenicity through activating sonic hedgehog signaling pathway. J Biol Chem. 2012; 287(11):7845-58. PMC: 3318742. DOI: 10.1074/jbc.M111.315416. View