title: 3,5,3'triiodo-L-thyronine induces SREBP-1 expression by non-genomic actions in human HEP G2 cells.
abstract: Liver is an important target for thyroid hormone actions. T(3) exerts its effects by two mechanisms: (i) Genomic actions consisting of T(3) link to nuclear receptors that bind responsive elements in the promoter of target genes, (ii) non-genomic actions including integrin αvb3 receptor-mediated MAPK/ERK and PI3K/Akt/mTOR-C1 activation. SREBP-1a, SREBP-1c, and SREBP-2 are transcription factors involved in the regulation of lipogenic genes. We show in Hep G2 cells that T(3) determined a dose- and time-dependent increase in the level of the precursor form of SREBP-1 without affecting SREBP-1 mRNA abundance. T(3) also induced phosphorylation of ERK1/2, Akt and of mTOR-C1 target S6K-P70, and the cytosol-to-membrane translocation of PKC-α. Modulation of SREBP-1 protein level by T(3) was dependent on MAPK/ERK, PI3K/Akt/mTOR-C1 pathway activation since the MEK inhibitor PD98059 or the PI3K inhibitor LY294002 abolished the stimulatory effect of T(3) . Conversely, the effect of T(3) on SREBP-1 level was enhanced by using rapamycin, mTOR-C1 inhibitor. These data suggest a negative control of mTOR-C1 target S6K-P70 on PI3K/Akt pathway. The effect of T(3) on SREBP-1 content increased also by using PKC inhibitors. These inhibitors increased the action of T(3) on Akt phosphorylation suggesting that conventional PKCs may work as negative regulators of the T(3) -dependent SREBP-1 increase. T(3) effects were partially abrogated by tetrac, an inhibitor of the T(3) -αvβ3 receptor interaction and partially evoked by T(3) analog T(3) -agarose. These findings support a model in which T(3) activates intracellular signaling pathways which may be involved in the increment of SREBP-1 level through an IRES-mediated translation mechanism.
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, Lecce, Italy. gabriele.gnoni@unisalento.it
authors.forename: Gabriele V
authors.initials: GV
authors.lastname: Gnoni
authors.forename: Alessio
authors.initials: A
authors.lastname: Rochira
authors.forename: Antonella
authors.initials: A
authors.lastname: Leone
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Damiano
authors.forename: Santo
authors.initials: S
authors.lastname: Marsigliante
authors.forename: Luisa
authors.initials: L
authors.lastname: Siculella
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025461:Feedback, Physiological; D056945:Hep G2 Cells; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D046912:Multiprotein Complexes; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014284:Triiodothyronine / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D039302:Integrin alphaVbeta3; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011506:Proteins; D012333:RNA, Messenger; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014284:Triiodothyronine; D058539:Phosphatidylinositol 3-Kinase; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3