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: KyeongJin Kim, Li Qiang, Matthew S Hayden, David P Sparling, Nicole H Purcell, Utpal B Pajvani
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 10255 (Jan 08 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 26743335 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Blood Glucose
• Insulin
• Multiprotein Complexes
• Regulatory-Associated Protein of mTOR
• Rptor protein, mouse
• Triglycerides
• beta-Transducin Repeat-Containing Proteins
• Mechanistic Target of Rapamycin Complex 1
• Oncogene Protein v-akt
• TOR Serine-Threonine Kinases
• Phosphoprotein Phosphatases

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Animals
• Blood Glucose (metabolism)
• Blotting, Western
• Chromatography, Gel
• Diet, High-Fat
• Fatty Liver (genetics, metabolism)
• Hepatocytes (metabolism)
• Immunoprecipitation
• Insulin (metabolism)
• Lipogenesis (genetics)
• Liver (metabolism)
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Multiprotein Complexes
• Non-alcoholic Fatty Liver Disease (genetics, metabolism)
• Obesity (genetics, metabolism)
• Oncogene Protein v-akt (metabolism)
• Phosphoprotein Phosphatases (metabolism)
• Regulatory-Associated Protein of mTOR
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• TOR Serine-Threonine Kinases
• Triglycerides (metabolism)
• beta-Transducin Repeat-Containing Proteins (metabolism)