Rochira Alessio, Damiano Fabrizio, Marsigliante Santo, Gnoni Gabriele V, Siculella Luisa
Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Science and Technologies, University of Salento, Via Prov. le Lecce-Monteroni, Lecce 73100, Italy.
Biochim Biophys Acta. 2013 Dec;1831(12):1679-89. doi: 10.1016/j.bbalip.2013.08.003. Epub 2013 Aug 13.
Thyroid hormone 3,5,3'-triiodo-l-thyronine (T3) is known to affect cell metabolism through both the genomic and non-genomic actions. Recently, we demonstrated in HepG2 cells that T3 controls the expression of SREBP-1, a transcription factor involved in the regulation of lipogenic genes. This occurs by activation of a cap-independent translation mechanism of its mRNA. Such a process is dependent on non-genomic activation of both MAPK/ERK and PI3K/Akt pathways. The physiological role of 3,5-diiodo-l-thyronine (T2), previously considered only as a T3 catabolite, is of growing interest. Evidences have been reported that T2 rapidly affects some metabolic pathways through non-genomic mechanisms. Here, we show that T2, unlike T3, determines the block of proteolytic cleavage of SREBP-1 in HepG2 cells, without affecting its expression at the transcriptional or translational level. Consequently, Fatty Acid Synthase expression is reduced. T2 effects depend on the concurrent activation of MAPKs ERK and p38, of Akt and PKC-δ pathways. Upon the activation of these signals, apoptosis of HepG2 cells seems to occur, starting at 12h of T2 treatment. PKC-δ appears to act as a switch between p38 activation and Akt suppression, suggesting that this PKC may function as a controller in the balance of pro-apoptotic (p38) and anti-apoptotic (Akt) signals in HepG2 cells.
甲状腺激素3,5,3'-三碘-L-甲状腺原氨酸（T3）已知可通过基因组和非基因组作用影响细胞代谢。最近，我们在HepG2细胞中证明，T3控制SREBP-1的表达，SREBP-1是一种参与脂肪生成基因调控的转录因子。这是通过激活其mRNA的非帽依赖性翻译机制实现的。这样的过程依赖于MAPK/ERK和PI3K/Akt途径的非基因组激活。3,5-二碘-L-甲状腺原氨酸（T2）的生理作用越来越受到关注，T2以前仅被视为T3的分解代谢产物。已有报道表明，T2通过非基因组机制迅速影响一些代谢途径。在这里，我们表明，与T3不同，T2可导致HepG2细胞中SREBP-1的蛋白水解切割受阻，而不影响其在转录或翻译水平的表达。因此，脂肪酸合酶的表达降低。T2的作用取决于MAPKs ERK和p38、Akt和PKC-δ途径的同时激活。在这些信号激活后，HepG2细胞的凋亡似乎在T2处理12小时后开始发生。PKC-δ似乎在p38激活和Akt抑制之间起开关作用，表明该PKC可能在HepG2细胞中促凋亡（p38）和抗凋亡（Akt）信号的平衡中起控制器的作用。
