Objective The AAA+ ATPase Reptin is overexpressed in hepatocellular carcinoma and preclinical studies indicate that it could be a relevant therapeutic target. However, its physiological and pathophysiological roles in vivo remain unknown. This study aimed to determine the role of Reptin in mammalian adult liver.
Design and results We generated an inducible liver-specific Reptin knockout (RepinLKO) mouse model. Following Reptin invalidation, mice displayed decreased body and fat mass, hypoglycaemia and hypolipidaemia. This was associated with decreased hepatic mTOR protein abundance. Further experiments in primary hepatocytes demonstrated that Reptin maintains mTOR protein level through its ATPase activity. Unexpectedly, loss or inhibition of Reptin induced an opposite effect on mTORC1 and mTORC2 signalling, with: (1) strong inhibition of hepatic mTORC1 activity, likely responsible for the reduction of hepatocytes cell size, for decreased de novo lipogenesis and cholesterol transcriptional programmes and (2) enhancement of mTORC2 activity associated with inhibition of the gluconeogenesis transcriptional programme and hepatic glucose production. Consequently, the role of hepatic Reptin in the pathogenesis of insulin resistance (IR) and non-alcoholic fatty liver disease consecutive to a high-fat diet was investigated. We found that Reptin deletion completely rescued pathological phenotypes associated with IR, including glucose intolerance, hyperglycaemia, hyperlipidaemia and hepatic steatosis.
Conclusion We show here that the AAA +ATPase Reptin is a regulator of mTOR signalling in the liver and global glucido-lipidic homeostasis. Inhibition of hepatic Reptin expression or activity represents a new therapeutic perspective for metabolic syndrome.
- diabetes mellitus
- fatty liver
- lipid metabolism
- glucose metabolism
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Contributors SB-T and JR conceived and designed the study, analysed and interpreted the data. SB-T, JJ, N A-C collected and analysed the data. NS, PC, CH, CB, NP-L and FB participated in data acquisition. RP and MDC carried out the generation of Reptinlox/lox mouse model. PD, DC and CP contributed to the analysis of the data. SB-T, JJ and JR drafted the manuscript. All authors revised the manuscript and approved it.
Funding This work was supported by grants from Inserm, la ‘Ligue Nationale Contre le Cancer’ (Equipe Labélisée Ligue Contre le Cancer 2011) and INCa (PLBIO10-155). JJ was a recipient of PhD fellowship from la Ligue Nationale Contre le Cancer (GB/MA/CD-11281). SB-T was supported by a grant from la ‘Fondation pour la Recherche medicale’ (FRM SFP20121226380). DC was supported by Inserm, Aquitaine Region and ANR-10-EQX-008-1 OPTOPATH. NS was supported by INSERM/Aquitaine Region PhD fellowship and FRM PhD fellowship FDT20150532545. CP is supported by grants from FRM (Foundation for the Medical Research, DEQ20150331744) and from National Agency for Research (ANR) (ANR-15-CE14-0026-Hepatokind).
Competing interests None declared.
Ethics approval All procedures were carried out according to the French guidelines for the care and use of experimental animals and approved by the C2EA-50 University of Bordeaux Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The additional data on human patients we provide in the revised version of our manuscript were generated from reanalysis of data available on Gene Expression Omnibus database.
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