mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2

• Published in: Nature communications 2016-01, Vol.7 (1), p.10255-10255, Article 10255
• Main Authors: Kim, KyeongJin, Qiang, Li, Hayden, Matthew S., Sparling, David P., Purcell, Nicole H., Pajvani, Utpal B.
• Format: Article
• Language: English
• Subjects: 631/80/86; 692/308; 692/699/1503/1607; Adaptor Proteins, Signal Transducing - genetics; Animals; beta-Transducin Repeat-Containing Proteins - metabolism; Blood Glucose - metabolism; Blotting, Western; Chromatography, Gel; Diet, High-Fat; Fatty Liver - genetics; Fatty Liver - metabolism; Hepatocytes - metabolism; Humanities and Social Sciences; Immunoprecipitation; Insulin - metabolism; Lipogenesis - genetics; Liver - metabolism; Mechanistic Target of Rapamycin Complex 1; Mice; multidisciplinary; Multiprotein Complexes; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Obesity - genetics; Obesity - metabolism; Oncogene Protein v-akt - metabolism; Phosphoprotein Phosphatases - metabolism; Regulatory-Associated Protein of mTOR; Reverse Transcriptase Polymerase Chain Reaction; Science; Science (multidisciplinary); Signal Transduction; TOR Serine-Threonine Kinases; Triglycerides - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10255

Mechanistic target of rapamycin complex 1 (mTORC1), defined by the presence of Raptor, is an evolutionarily conserved and nutrient-sensitive regulator of cellular growth and other metabolic processes. To date, all known functions of Raptor involve its scaffolding mTOR kinase with substrate. Here we report that mTORC1-independent (‘free’) Raptor negatively regulates hepatic Akt activity and lipogenesis. Free Raptor levels in liver decline with age and in obesity; restoration of free Raptor levels reduces liver triglyceride content, through reduced β-TrCP-mediated degradation of the Akt phosphatase, PHLPP2. Commensurately, forced PHLPP2 expression ameliorates hepatic steatosis in diet-induced obese mice. These data suggest that the balance of free and mTORC1-associated Raptor governs hepatic lipid accumulation, and uncover the potentially therapeutic role of PHLPP2 activators in non-alcoholic fatty liver disease. The protein raptor is a subunit of the mTORC signalling complex. Here the authors show that Raptor also exists in a free form, unbound to mTORC, and that this free Raptor negatively regulates hepatic Akt activity and lipid metabolism in mice via a mechanism involving the Akt phosphatase PHLPP2.