3,5,3′triiodo-L-thyronine induces SREBP-1 expression by non-genomic actions in human HEP G2 cells
✍ Scribed by Gabriele V. Gnoni; Alessio Rochira; Antonella Leone; Fabrizio Damiano; Santo Marsigliante; Luisa Siculella
- Book ID
- 102313160
- Publisher
- John Wiley and Sons
- Year
- 2012
- Tongue
- English
- Weight
- 433 KB
- Volume
- 227
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
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 avb3 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-a. 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 -avb3 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.