mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2

作者：Kim KyeongJin; Qiang Li; Hayden Matthew S; Sparling David P; Purcell Nicole H; Pajvani Utpal B^*

来源：Nature Communications, 2016, 7(1): 10255.

DOI：10.1038/ncomms10255

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 beta-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.

• 出版日期2016-1