3,5,3′triiodo‐L‐thyronine induces SREBP‐1 expression by non‐genomic actions in human HEP G2 cells

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. J. Cell. Physiol. 227: 2388–2397, 2012. © 2011 Wiley Periodicals, Inc.