title: mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2.
abstract: 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.
authors.affiliation: Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: KyeongJin
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qiang
authors.affiliation: Department of Dermatology, Columbia University, New York, New York 10032, USA.|Department of Microbiology &Immunology, Columbia University, New York, New York 10032, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Hayden
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York 10032, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Sparling
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Nicole H
authors.initials: NH
authors.lastname: Purcell
authors.affiliation: Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Utpal B
authors.initials: UB
authors.lastname: Pajvani
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002850:Chromatography, Gel; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014280:Triglycerides / Q000378:metabolism; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D007328:Insulin; D046912:Multiprotein Complexes; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D014280:Triglycerides; D044844:beta-Transducin Repeat-Containing Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases