mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 26743335.
- Also identified by DOI 10.1038/ncomms10255 and PMC identifier 4729872.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Adaptor Proteins, Signal Transducing
- Hepatocytes
- Lipogenesis
- Liver
- Non-alcoholic Fatty Liver Disease
- Obesity
- Oncogene Protein v-akt