RT Journal Article
SR Electronic
T1 Liver Reptin/RUVBL2 controls glucose and lipid metabolism with opposite actions on mTORC1 and mTORC2 signalling
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 2192
OP 2203
DO 10.1136/gutjnl-2017-314208
VO 67
IS 12
A1 Joaquim Javary
A1 Nathalie Allain-Courtois
A1 Nicolas Saucisse
A1 Pierre Costet
A1 Capucine Heraud
A1 Fadila Benhamed
A1 Rémi Pierre
A1 Corinne Bure
A1 Nestor Pallares-Lupon
A1 Marcio Do Cruzeiro
A1 Catherine Postic
A1 Daniela Cota
A1 Pierre Dubus
A1 Jean Rosenbaum
A1 Samira Benhamouche-Trouillet
YR 2018
UL http://gut.bmj.com/content/67/12/2192.abstract
AB 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.