Background: 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-alpha(TNF-alpha). 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. Aim: To investigate the possible role of TNF-alpha and JAK/STAT pathway on de novo lipogenesis and PCSK9 expression in HepG2 cells. Results: A 24-h TNF-alpha(10ng/mL) treatment induced SOCS3 and PCSK9 mRNA (7 fold and 2 fold, respectively) and protein (+150% and +41%, respectively) levels. siRNA anti-SOCS3 or anti-STAT3 completely blocked the effect of TNF-alpha on PCSK9 induction and siRNA anti-STAT3 blocked that of SOCS3. In response to TNF-alphawe observed a significant induction of mRNA levels of key enzymes involved in the de novo lipogenesis stearoyl-CoA desaturase (SCD-1), apoB and fatty-acid synthase (FAS; 2.11±0.43, 1.60±0.33 and 1.39±0.21 fold, respectively). These responses were reversed in HepG2 cells transfected with siRNA STAT3. The involvement of SOCS3 pathway was further confirmed by using HepG2 cells overexpressing SOCS3 protein (HepG2SOCS3). These cells compared to HepG2 wild type showed higher levels of PCSK9 (3.48±0.35 fold), FAS, SCD-1, and apo-B mRNA as well as that of PCSK9 (1.53 fold), SCD-1 (3.81) and apoB (3.47 fold) proteins. SOCS3 overexpression resulted in a higher intracellular TG levels content. Conclusions: Our data demonstrated PCSK9 to be a gene involved in lipid metabolism regulated by TNF-alpha, in a SOCS3-dependent manner.

TNF-alpha induces Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) expression in hepatic HepG2 cell line in a SOCS-3-dependent manner / M. Ruscica, C. Ricci, C. Macchi, P. Magni, J. Liu, A. Corsini, N. Ferri. - In: ATHEROSCLEROSIS. - ISSN 0021-9150. - 252:(2016 May 31), pp. e197-e198. ((Intervento presentato al 84. convegno European Atherosclerosis Society Congress (EAS) tenutosi a Innsbruck nel 2016 [10.1016/j.atherosclerosis.2016.07.107].

TNF-alpha induces Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) expression in hepatic HepG2 cell line in a SOCS-3-dependent manner

M. Ruscica
Primo
;
C. Ricci
Secondo
;
C. Macchi;P. Magni;A. Corsini
Penultimo
;
N. Ferri
Ultimo
2016

Abstract

Background: 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-alpha(TNF-alpha). 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. Aim: To investigate the possible role of TNF-alpha and JAK/STAT pathway on de novo lipogenesis and PCSK9 expression in HepG2 cells. Results: A 24-h TNF-alpha(10ng/mL) treatment induced SOCS3 and PCSK9 mRNA (7 fold and 2 fold, respectively) and protein (+150% and +41%, respectively) levels. siRNA anti-SOCS3 or anti-STAT3 completely blocked the effect of TNF-alpha on PCSK9 induction and siRNA anti-STAT3 blocked that of SOCS3. In response to TNF-alphawe observed a significant induction of mRNA levels of key enzymes involved in the de novo lipogenesis stearoyl-CoA desaturase (SCD-1), apoB and fatty-acid synthase (FAS; 2.11±0.43, 1.60±0.33 and 1.39±0.21 fold, respectively). These responses were reversed in HepG2 cells transfected with siRNA STAT3. The involvement of SOCS3 pathway was further confirmed by using HepG2 cells overexpressing SOCS3 protein (HepG2SOCS3). These cells compared to HepG2 wild type showed higher levels of PCSK9 (3.48±0.35 fold), FAS, SCD-1, and apo-B mRNA as well as that of PCSK9 (1.53 fold), SCD-1 (3.81) and apoB (3.47 fold) proteins. SOCS3 overexpression resulted in a higher intracellular TG levels content. Conclusions: Our data demonstrated PCSK9 to be a gene involved in lipid metabolism regulated by TNF-alpha, in a SOCS3-dependent manner.
Settore BIO/14 - Farmacologia
Settore MED/04 - Patologia Generale
Settore MED/05 - Patologia Clinica
31-mag-2016
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/467209
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