Abstract

Liver is an important target for thyroid hormone actions. T3 exerts its effects by two mechanisms: (i) Genomic actions consisting of T3 linkto nuclear receptors that bind responsive elements in the promoter of target genes, (ii) non-genomic actions including integrin avb3receptor-mediated MAPK/ERK and PI3K/Akt/mTOR-C1 activation. SREBP-1a, SREBP-1c, and SREBP-2 are transcription factors involvedin the regulation of lipogenic genes. We show in Hep G2 cells that T3 determined a dose- and time-dependent increase in the level of theprecursor form of SREBP-1 without affecting SREBP-1 mRNA abundance. T3 also induced phosphorylation of ERK1/2, Akt and of mTORC1target S6K-P70, and the cytosol-to-membrane translocation of PKC-a. Modulation of SREBP-1 protein level by T3 was dependent onMAPK/ERK, PI3K/Akt/mTOR-C1 pathway activation since the MEK inhibitor PD98059 or the PI3K inhibitor LY294002 abolished thestimulatory effect of T3. Conversely, the effect of T3 on SREBP-1 level was enhanced by using rapamycin, mTOR-C1 inhibitor. These datasuggest a negative control of mTOR-C1 target S6K-P70 on PI3K/Akt pathway. The effect of T3 on SREBP-1 content increased also by usingPKC inhibitors. These inhibitors increased the action of T3 on Akt phosphorylation suggesting that conventional PKCs may work asnegative regulators of the T3-dependent SREBP-1 increase. T3 effects were partially abrogated by tetrac, an inhibitor of the T3-avb3receptor interaction and partially evoked by T3 analog T3-agarose. These findings support a model in which T3 activates intracellularsignaling pathways which may be involved in the increment of SREBP-1 level through an IRES-mediated translation mechanism.J. Cell. Physiol. 227: 2388-2397, 2012.

Autore Pugliese

• Leone Antonella

Tutti gli autori

• Gnoni G.V.; Rochira A.; Leone A.; Damiano F.; Marsiliante S.; Siculella L.

Titolo volume/Rivista

Journal of cellular physiology

Anno di pubblicazione

2012

ISSN

1097-4652

ISBN

Non Disponibile

Numero di citazioni Wos

Nessuna citazione

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Settori ERC

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Codici ASJC

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