{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T11:23:51Z","timestamp":1791113031850,"version":"4.1.0"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2011,3,29]],"date-time":"2011-03-29T00:00:00Z","timestamp":1301356800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0018075","type":"journal-article","created":{"date-parts":[[2011,3,29]],"date-time":"2011-03-29T20:55:47Z","timestamp":1301432147000},"page":"e18075","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":68,"title":["Tuberous Sclerosis Complex-1 Deficiency Attenuates Diet-Induced Hepatic Lipid Accumulation"],"prefix":"10.1371","volume":"6","author":[{"given":"Heidi L.","family":"Kenerson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew M.","family":"Yeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond S.","family":"Yeung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2011,3,29]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/ncpgasthep0084","article-title":"Mechanisms of Disease: pathogenesis of nonalcoholic fatty liver disease.","volume":"2","author":"AJ Sanyal","year":"2005","journal-title":"Nat Clin Pract Gastroenterol Hepatol"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/ncpendmet0190","article-title":"Mechanisms of Disease: hepatic steatosis in type 2 diabetes\u2013pathogenesis and clinical relevance.","volume":"2","author":"M Roden","year":"2006","journal-title":"Nat Clin Pract Endocrinol Metab"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1056\/NEJMoa0907929","article-title":"Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.","volume":"362","author":"AJ Sanyal","year":"2010","journal-title":"N Engl J Med"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1042\/BST0320812","article-title":"Uncoupling insulin signalling by serine\/threonine phosphorylation: a molecular basis for insulin resistance.","volume":"32","author":"Y Zick","year":"2004","journal-title":"Biochem Soc Trans"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/S0968-0004(97)01061-X","article-title":"Phosphoinositide 3-kinases: a conserved family of signal transducers.","volume":"22","author":"B Vanhaesebroeck","year":"1997","journal-title":"Trends Biochem Sci"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/S0163-7258(02)00193-6","article-title":"Inhibition of protein kinase B\/Akt. implications for cancer therapy.","volume":"93","author":"MM Hill","year":"2002","journal-title":"Pharmacol Ther"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.cmet.2007.12.009","article-title":"Selective versus total insulin resistance: a pathogenic paradox.","volume":"7","author":"MS Brown","year":"2008","journal-title":"Cell Metab"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"R1046","DOI":"10.1016\/j.cub.2009.09.058","article-title":"An emerging role of mTOR in lipid biosynthesis.","volume":"19","author":"M Laplante","year":"2009","journal-title":"Curr Biol"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.cmet.2008.07.007","article-title":"SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth.","volume":"8","author":"T Porstmann","year":"2008","journal-title":"Cell Metab"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.molcel.2010.06.022","article-title":"Activation of a metabolic gene regulatory network downstream of mTOR complex 1.","volume":"39","author":"K Duvel","year":"2010","journal-title":"Mol Cell"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1016\/j.metabol.2007.06.016","article-title":"The mammalian target of rapamycin regulates lipid metabolism in primary cultures of rat hepatocytes.","volume":"56","author":"NF Brown","year":"2007","journal-title":"Metabolism"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s12079-007-0011-1","article-title":"Role of the PI3-kinase\/mTor pathway in the regulation of the stearoyl CoA desaturase (SCD1) gene expression by insulin in liver.","volume":"1","author":"D Mauvoisin","year":"2007","journal-title":"J Cell Commun Signal"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"e6189","DOI":"10.1371\/journal.pone.0006189","article-title":"Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway.","volume":"4","author":"HH Zhang","year":"2009","journal-title":"PLoS One"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1073\/pnas.0914798107","article-title":"Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis.","volume":"107","author":"S Li","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1073\/pnas.0308617100","article-title":"Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected].","volume":"101","author":"B Stiles","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1172\/JCI20513","article-title":"Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas.","volume":"113","author":"Y Horie","year":"2004","journal-title":"J Clin Invest"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1126\/science.1120781","article-title":"The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin.","volume":"310","author":"RJ Shaw","year":"2005","journal-title":"Science"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.2337\/diabetes.52.12.2905","article-title":"Hepatic Akt activation induces marked hypoglycemia, hepatomegaly, and hypertriglyceridemia with sterol regulatory element binding protein involvement.","volume":"52","author":"H Ono","year":"2003","journal-title":"Diabetes"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1172\/JCI29528","article-title":"Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2.","volume":"117","author":"O Le Bacquer","year":"2007","journal-title":"J Clin Invest"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1172\/JCI118951","article-title":"Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a.","volume":"98","author":"H Shimano","year":"1996","journal-title":"J Clin Invest"},{"key":"ref21","article-title":"Improved insulin sensitivity by caloric restriction is associated with reduction of ERK and p70 S6K activities in the liver of obese Zucker rats.","author":"Y Zheng","year":"2009","journal-title":"J Endocrinol"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/nature02866","article-title":"Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity.","volume":"431","author":"SH Um","year":"2004","journal-title":"Nature"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.1007\/s00125-006-0439-5","article-title":"Sustained activation of the mammalian target of rapamycin nutrient sensing pathway is associated with hepatic insulin resistance, but not with steatosis, in mice.","volume":"49","author":"E Korsheninnikova","year":"2006","journal-title":"Diabetologia"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.ceb.2005.09.009","article-title":"Growing roles for the mTOR pathway.","volume":"17","author":"D Sarbassov dos","year":"2005","journal-title":"Curr Opin Cell Biol"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S0092-8674(01)00333-6","article-title":"Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size.","volume":"105","author":"CJ Potter","year":"2001","journal-title":"Cell"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/ncb847","article-title":"Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling.","volume":"4","author":"X Gao","year":"2002","journal-title":"Nat Cell Biol"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"30958","DOI":"10.1074\/jbc.M202678200","article-title":"Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM).","volume":"277","author":"EA Goncharova","year":"2002","journal-title":"J Biol Chem"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/S0960-9822(03)00506-2","article-title":"Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb.","volume":"13","author":"AR Tee","year":"2003","journal-title":"Curr Biol"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/nature04869","article-title":"Ras, PI(3)K and mTOR signalling controls tumour cell growth.","volume":"441","author":"RJ Shaw","year":"2006","journal-title":"Nature"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"35647","DOI":"10.1074\/jbc.274.50.35647","article-title":"Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin.","volume":"274","author":"M Nellist","year":"1999","journal-title":"J Biol Chem"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1083\/jcb.200507119","article-title":"Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning.","volume":"173","author":"SL Cai","year":"2006","journal-title":"J Cell Biol"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1083\/jcb.200403069","article-title":"The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins.","volume":"166","author":"LS Harrington","year":"2004","journal-title":"J Cell Biol"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0009-9120(93)90015-X","article-title":"Enzymatic determination of triglyceride, free cholesterol, and total cholesterol in tissue lipid extracts.","volume":"26","author":"TP Carr","year":"1993","journal-title":"Clin Biochem"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1111\/j.1742-7843.2009.00427.x","article-title":"Long-term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed KK\/HlJ mice.","volume":"105","author":"GR Chang","year":"2009","journal-title":"Basic Clin Pharmacol Toxicol"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.2337\/db09-1324","article-title":"Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue.","volume":"59","author":"VP Houde","year":"2010","journal-title":"Diabetes"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"E115","DOI":"10.1152\/ajpendo.00317.2005","article-title":"The adipose tissue triglyceride lipase ATGL\/PNPLA2 is downregulated by insulin and TNF-alpha in 3T3-L1 adipocytes and is a target for transactivation by PPARgamma.","volume":"291","author":"JY Kim","year":"2006","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"13296","DOI":"10.1074\/jbc.C800241200","article-title":"FoxO1 controls insulin-dependent adipose triglyceride lipase (ATGL) expression and lipolysis in adipocytes.","volume":"284","author":"P Chakrabarti","year":"2009","journal-title":"J Biol Chem"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1007\/s11892-009-0034-5","article-title":"The role of FOXO in the regulation of metabolism.","volume":"9","author":"DN Gross","year":"2009","journal-title":"Curr Diab Rep"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.1073\/pnas.1000323107","article-title":"mTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis.","volume":"107","author":"M Laplante","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.2353\/ajpath.2010.090931","article-title":"The critical role of AKT2 in hepatic steatosis induced by PTEN loss.","volume":"176","author":"L He","year":"2010","journal-title":"Am J Pathol"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.cmet.2009.10.004","article-title":"Akt2 is required for hepatic lipid accumulation in models of insulin resistance.","volume":"10","author":"KF Leavens","year":"2009","journal-title":"Cell Metab"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1186\/bcr2558","article-title":"Key signalling nodes in mammary gland development and cancer. Signalling downstream of PI3 kinase in mammary epithelium: a play in 3 Akts.","volume":"12","author":"JA Wickenden","year":"2010","journal-title":"Breast Cancer Res"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1053\/j.seminoncol.2009.10.011","article-title":"Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth.","volume":"36","author":"JJ Gibbons","year":"2009","journal-title":"Semin Oncol"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.cmet.2007.11.013","article-title":"Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis.","volume":"7","author":"SB Biddinger","year":"2008","journal-title":"Cell Metab"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.molcel.2006.03.029","article-title":"Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt\/PKB.","volume":"22","author":"D Sarbassov dos","year":"2006","journal-title":"Mol Cell"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S1262-3636(08)74600-7","article-title":"Insulin resistance and steatosis in humans.","volume":"34","author":"J Capeau","year":"2008","journal-title":"Diabetes Metab"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1172\/JCI34275","article-title":"Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice.","volume":"118","author":"C Postic","year":"2008","journal-title":"J Clin Invest"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"5885","DOI":"10.1074\/jbc.M807906200","article-title":"A phosphorylation cascade controls the degradation of active SREBP1.","volume":"284","author":"MT Bengoechea-Alonso","year":"2009","journal-title":"J Biol Chem"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"10105","DOI":"10.1074\/jbc.M600272200","article-title":"FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression.","volume":"281","author":"W Zhang","year":"2006","journal-title":"J Biol Chem"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"5641","DOI":"10.1210\/en.2006-0541","article-title":"Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism.","volume":"147","author":"S Qu","year":"2006","journal-title":"Endocrinology"},{"key":"ref51","first-page":"2464","article-title":"Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism.","volume":"116","author":"M Matsumoto","year":"2006","journal-title":"J Clin Invest"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/ng1951","article-title":"The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy.","volume":"39","author":"J Fischer","year":"2007","journal-title":"Nat Genet"}],"container-title":["PLoS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0018075","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2018,10,23]],"date-time":"2018-10-23T09:25:29Z","timestamp":1540286729000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0018075"}},"subtitle":[],"editor":[{"given":"Nai Sum","family":"Wong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2011,3,29]]},"references-count":52,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2011,3,29]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0018075","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,3,29]]}}}