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dc.contributor.authorDanai, Laura V.
dc.contributor.authorGuilherme, Adilson L.
dc.contributor.authorGuntur, Kalyani V. P.
dc.contributor.authorStraubhaar, Juerg R.
dc.contributor.authorNicoloro, Sarah M.
dc.contributor.authorCzech, Michael P.
dc.date2022-08-11T08:08:30.000
dc.date.accessioned2022-08-23T15:57:43Z
dc.date.available2022-08-23T15:57:43Z
dc.date.issued2013-10-01
dc.date.submitted2015-01-15
dc.identifier.citationJ Lipid Res. 2013 Oct;54(10):2697-707. doi: 10.1194/jlr.M038802. Epub 2013 Aug 7. <a href="http://dx.doi.org/10.1194/jlr.M038802">Link to article on publisher's site</a>
dc.identifier.issn0022-2275 (Linking)
dc.identifier.doi10.1194/jlr.M038802
dc.identifier.pmid23924694
dc.identifier.urihttp://hdl.handle.net/20.500.14038/30267
dc.description.abstractAdipose tissue lipogenesis is paradoxically impaired in human obesity, promoting ectopic triglyceride (TG) deposition, lipotoxicity, and insulin resistance. We previously identified mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4), a sterile 20 protein kinase reported to be upstream of c-Jun NH2-terminal kinase (JNK) signaling, as a novel negative regulator of insulin-stimulated glucose transport in adipocytes. Using full-genome microarray analysis we uncovered a novel role for Map4k4 as a suppressor of lipid synthesis. We further report here the surprising finding that Map4k4 suppresses adipocyte lipogenesis independently of JNK. Thus, while Map4k4 silencing in adipocytes enhances the expression of lipogenic enzymes, concomitant with increased conversion of (14)C-glucose and (14)C-acetate into TGs and fatty acids, JNK1 and JNK2 depletion causes the opposite effects. Furthermore, high expression of Map4k4 fails to activate endogenous JNK, while Map4k4 depletion does not attenuate JNK activation by tumor necrosis factor alpha. Map4k4 silencing in cultured adipocytes elevates both the total protein expression and cleavage of sterol-regulated element binding protein-1 (Srebp-1) in a rapamycin-sensitive manner, consistent with Map4k4 signaling via mechanistic target of rapamycin complex 1 (mTORC1). We show Map4k4 depletion requires Srebp-1 upregulation to increase lipogenesis and further show that Map4k4 promotes AMP-protein kinase (AMPK) signaling and the phosphorylation of mTORC1 binding partner raptor (Ser792) to inhibit mTORC1. Our results indicate that Map4k4 inhibits adipose lipogenesis by suppression of Srebp-1 in an AMPK- and mTOR-dependent but JNK-independent mechanism.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=23924694&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1194/jlr.M038802
dc.subject3T3-L1 Cells
dc.subjectAMP-Activated Protein Kinases
dc.subjectAdipocytes
dc.subjectAnimals
dc.subjectEnzyme Activation
dc.subjectGene Expression
dc.subjectGene Knockdown Techniques
dc.subject*Lipogenesis
dc.subject*MAP Kinase Signaling System
dc.subjectMice
dc.subjectObesity
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectSterol Regulatory Element Binding Protein 1
dc.subjectTOR Serine-Threonine Kinases
dc.subjectTranscriptional Activation
dc.subjectTriglycerides
dc.subjectBiochemistry
dc.subjectCellular and Molecular Physiology
dc.subjectMolecular Biology
dc.titleMap4k4 suppresses Srebp-1 and adipocyte lipogenesis independent of JNK signaling
dc.typeJournal Article
dc.source.journaltitleJournal of lipid research
dc.source.volume54
dc.source.issue10
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/520
dc.identifier.contextkey6532246
html.description.abstract<p>Adipose tissue lipogenesis is paradoxically impaired in human obesity, promoting ectopic triglyceride (TG) deposition, lipotoxicity, and insulin resistance. We previously identified mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4), a sterile 20 protein kinase reported to be upstream of c-Jun NH2-terminal kinase (JNK) signaling, as a novel negative regulator of insulin-stimulated glucose transport in adipocytes. Using full-genome microarray analysis we uncovered a novel role for Map4k4 as a suppressor of lipid synthesis. We further report here the surprising finding that Map4k4 suppresses adipocyte lipogenesis independently of JNK. Thus, while Map4k4 silencing in adipocytes enhances the expression of lipogenic enzymes, concomitant with increased conversion of (14)C-glucose and (14)C-acetate into TGs and fatty acids, JNK1 and JNK2 depletion causes the opposite effects. Furthermore, high expression of Map4k4 fails to activate endogenous JNK, while Map4k4 depletion does not attenuate JNK activation by tumor necrosis factor alpha. Map4k4 silencing in cultured adipocytes elevates both the total protein expression and cleavage of sterol-regulated element binding protein-1 (Srebp-1) in a rapamycin-sensitive manner, consistent with Map4k4 signaling via mechanistic target of rapamycin complex 1 (mTORC1). We show Map4k4 depletion requires Srebp-1 upregulation to increase lipogenesis and further show that Map4k4 promotes AMP-protein kinase (AMPK) signaling and the phosphorylation of mTORC1 binding partner raptor (Ser792) to inhibit mTORC1. Our results indicate that Map4k4 inhibits adipose lipogenesis by suppression of Srebp-1 in an AMPK- and mTOR-dependent but JNK-independent mechanism.</p>
dc.identifier.submissionpathfaculty_pubs/520
dc.contributor.departmentProgram in Molecular Medicine
dc.source.pages2697-707


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