The suppressor of cytokine signaling (SOCS) proteins are negative regulators of the JAK/STAT pathway activated by pro-inflammatory cytokines, including the tumor necrosis factor-α (TNF-a). SOCS3 is also implicated in hypertriglyceridemia associated to insulin-resistance (IR). Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) levels are frequently found to be positively correlated to IR and plasma very low-density lipoprotein-triglycerides (VLDL-TG) concentrations. The present study aimed to investigate the possible role of TNF-α and JAK/STAT pathway on de novo lipogenesis and PCSK9 expression in HepG2 cells. TNF-a induced both SOCS3 and PCSK9 in a concentration-dependent manner. This effect was inhibited by transfection with siRNA anti-STAT3, suggesting the involvement of the JAK/STAT pathway. Retroviral overexpression of SOCS3 in HepG2 cells (HepG2SOCS3) strongly inhibited STAT3 phosphorylation and induced PCSK9 mRNA and protein, with no effect on its promoter activity. Consistently, siRNA anti-SOCS3 reduced PCSK9 mRNA levels while an opposite effect was observed with siRNA anti-STAT3. In addition, HepG2SOCS3 express higher mRNA levels of key enzymes involved in the de novo lipogenesis, such as fatty-acid synthase (FAS), stearoyl-CoA desaturase, and apo-B. These responses were associated with significant increase of SCD- 1 protein, activation of SREBP-1, accumulation of cellular TG, and secretion of apoB. HepG2SOCS3 shows lower phosphorylation levels of IRS-1 Tyr896 and Akt Ser473 in response to insulin. Finally, insulin stimulation produced an additive effect with SOCS3 overexpression, further inducing PCSK9, SREBP-1, FAS and apoB mRNA. In conclusion, our data candidate PCSK9 as a gene involved in lipid metabolism regulated by pro-inflammatory cytokine TNF-α, in a SOCS3 dependent manner.
Suppressor of cytokine signaling-3 (SOCS-3) induces proprotein convertase subtilisin kexin type 9 (PCSK9) expression in hepatic hepg2 cell line / C. Ricci, M. Ruscica, C. Macchi, P. Magni, R. Cristofani, J. Liu, A. Corsini, N. Ferri. - In: GIORNALE ITALIANO DELL'ARTERIOSCLEROSI. - ISSN 2240-4821. - 6:4(2015 Nov 22), pp. 44-44. ((Intervento presentato al 29. convegno Società Italiana per lo Studio della Aterosclerosi (SISA) tenutosi a Bologna nel 2015.
|Titolo:||Suppressor of cytokine signaling-3 (SOCS-3) induces proprotein convertase subtilisin kexin type 9 (PCSK9) expression in hepatic hepg2 cell line|
|Parole Chiave:||SOCS3; PCSK9; insulin-resistance|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
Settore MED/04 - Patologia Generale
Settore MED/05 - Patologia Clinica
Settore BIO/13 - Biologia Applicata
|Data di pubblicazione:||22-nov-2015|
|Appare nelle tipologie:||01 - Articolo su periodico|