| Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2. | |
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MedLine Citation:
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PMID: 22773877 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mammalian target of rapamycin complex 2 (mTORC2) is a key activator of protein kinases that act downstream of insulin and growth factor signaling. Here we report that mice lacking the essential mTORC2 component rictor in liver (Lrictor(KO)) are unable to respond normally to insulin. In response to insulin, Lrictor(KO) mice failed to inhibit hepatic glucose output. Lrictor(KO) mice also fail to develop hepatic steatosis on a high fat diet and manifest half-normal serum cholesterol levels. This is accompanied by lower levels of expression of SREBP-1c and SREBP-2 and genes of fatty acid and cholesterol biosynthesis. Lrictor(KO) mice had defects in insulin-stimulated Akt Ser-473 and Thr-308 phosphorylation, leading to decreased phosphorylation of Akt substrates FoxO, GSK-3β, PRAS40, AS160, and Tsc2. Lrictor(KO) mice also manifest defects in insulin-activated mTORC1 activity, evidenced by decreased S6 kinase and Lipin1 phosphorylation. Glucose intolerance and insulin resistance of Lrictor(KO) mice could be fully rescued by hepatic expression of activated Akt2 or dominant negative FoxO1. However, in the absence of mTORC2, forced Akt2 activation was unable to drive hepatic lipogenesis. Thus, we have identified an Akt-independent relay from mTORC2 to hepatic lipogenesis that separates the effects of insulin on glucose and lipid metabolism. |
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Authors:
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Minsheng Yuan; Elizabeth Pino; Lianfeng Wu; Michael Kacergis; Alexander A Soukas |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-07-07 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 287 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2012 Aug |
Date Detail:
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Created Date: 2012-08-27 Completed Date: 2012-11-19 Revised Date: 2013-05-07 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 29579-88 Citation Subset: IM |
Affiliation:
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Center for Human Genetics and Diabetes Unit, Department of Medicine, Massachusetts General Hospital, and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing
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genetics,
metabolism Animals Cholesterol / biosynthesis, genetics Fatty Acids / genetics, metabolism Forkhead Transcription Factors / genetics, metabolism GTPase-Activating Proteins / genetics, metabolism Gene Expression Regulation / physiology Glucose / genetics, metabolism Glycogen Synthase Kinase 3 / genetics, metabolism Hep G2 Cells Humans Insulin / genetics, metabolism Insulin Resistance / physiology Lipogenesis / physiology* Liver / metabolism* Mice Mice, Transgenic Phosphoproteins / genetics, metabolism Phosphorylation / physiology Proto-Oncogene Proteins c-akt / genetics, metabolism* Sterol Regulatory Element Binding Protein 1 / genetics, metabolism Sterol Regulatory Element Binding Protein 2 / genetics, metabolism Trans-Activators / genetics, metabolism* Transcription Factors / genetics, metabolism* Tumor Suppressor Proteins / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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K08 DK087941/DK/NIDDK NIH HHS; K08DK087941/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/AKT1S1 protein, human; 0/Adaptor Proteins, Signal Transducing; 0/CRTC2 protein, human; 0/Crtc2 protein, mouse; 0/FOXO1 protein, human; 0/Fatty Acids; 0/Forkhead Transcription Factors; 0/Foxo1 protein, mouse; 0/GTPase-Activating Proteins; 0/Insulin; 0/Phosphoproteins; 0/SREBF1 protein, human; 0/SREBF2 protein, human; 0/Srebf1 protein, mouse; 0/Srebf2 protein, mouse; 0/Sterol Regulatory Element Binding Protein 1; 0/Sterol Regulatory Element Binding Protein 2; 0/TBC1D4 protein, human; 0/Tbc1d4 protein, mouse; 0/Trans-Activators; 0/Transcription Factors; 0/Tumor Suppressor Proteins; 0/proline-rich Akt substrate, 40 kDa protein, mouse; 4JG2LF96VF/tuberous sclerosis complex 2 protein; 50-99-7/Glucose; 57-88-5/Cholesterol; EC 2.7.11.1/AKT2 protein, human; EC 2.7.11.1/Akt2 protein, mouse; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3 |
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