3,5-Diiodo-l-thyronine induces SREBP-1 proteolytic cleavage block and apoptosis in human hepatoma (Hepg2) cells.
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.
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.
Alessio
A
Rochira
Fabrizio
F
Damiano
Santo
S
Marsigliante
Gabriele V
GV
Gnoni
Luisa
L
Siculella
D017209:Apoptosis / Q000187:drug effects*; D004104:Diiodothyronines / Q000494:pharmacology*; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
D004104:Diiodothyronines; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014284:Triiodothyronine; C030103:3,5-diiodothyronine; D054890:Fatty Acid Synthase, Type I; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
3,5,3′-triiodo-l-thyronine; 3,5-Diiodothyronine; 3,5-diiodo-l-thyronine; 4,6-diamidino-2-phenylindole; Akt; Apoptosis; DAPI; ERK; FASN; FL; IRES; MAPK; PI3K; PKC; PKC-δ; RL; Renilla luciferase; SRB; SREBP; SREBP-1; T2; T3; TH; extracellular signal-regulated kinase; fatty acid synthase; firefly luciferase; internal ribosome entry site; mTOR-C1; mammalian target of rapamycin complex 1; mitogen activated protein kinase; p38MAPK; phosphoinositide 3-kinase; protein kinase C; sterol regulatory element binding protein; sulforhodamine B; thyroid hormone