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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Animals
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Blood Glucose / metabolism
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Blotting, Western
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Chromatography, Gel
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Diet, High-Fat
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Fatty Liver / genetics
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Fatty Liver / metabolism
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Hepatocytes / metabolism*
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Immunoprecipitation
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Insulin / metabolism
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Lipogenesis / genetics*
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Liver / metabolism*
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Multiprotein Complexes
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Non-alcoholic Fatty Liver Disease / genetics*
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Non-alcoholic Fatty Liver Disease / metabolism
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Obesity / genetics*
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Obesity / metabolism
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Oncogene Protein v-akt / metabolism*
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Phosphoprotein Phosphatases / metabolism
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Regulatory-Associated Protein of mTOR
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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TOR Serine-Threonine Kinases
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Triglycerides / metabolism
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beta-Transducin Repeat-Containing Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Blood Glucose
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Insulin
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Multiprotein Complexes
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Regulatory-Associated Protein of mTOR
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Rptor protein, mouse
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Triglycerides
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beta-Transducin Repeat-Containing Proteins
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Mechanistic Target of Rapamycin Complex 1
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Oncogene Protein v-akt
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TOR Serine-Threonine Kinases
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Phosphoprotein Phosphatases