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mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2

Kim, Kyeong Jin; Qiang, Li; Hayden, Matthew S.; Sparling, David P.; Purcell, Nicole H.; Pajvani, Utpal B.

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.

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Title
Nature Communications
DOI
https://doi.org/10.1038/ncomms10255

More About This Work

Academic Units
Medicine
Pathology and Cell Biology
Pediatrics
Microbiology and Immunology
Publisher
Nature Publishing Group
Published Here
September 16, 2016