biostudies-literatureKim KNIDDK NIH HHSNHLBI NIH HHS10255https://www.ebi.ac.uk/biostudies/studies/S-EPMC4729872biostudies-literatureUnknown7Mechanistic 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 hepaticNature communicationsmTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2.PMC4729872DK093604R01 HL114949K08 DK093604T32 DK065522P30 DK026687R01 DK103818R00 DK097455Hayden MSKim KQiang LSparling DPPurcell NHPajvani UBfalsemTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2.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 hepatic2016-01-01T00:00:00Z2016 Jan2025-04-04T03:42:29.126Z2019-03-27T02:07:44ZS-EPMC47298722674333510.1038/ncomms10255