Aim: Clinical, genetic and experimental evidence indicates that proprotein convertase subtilisin/kexin 9 (PCSK9) may be either a cause or an effect of metabolic syndrome (MetS). We have recently demonstrated that PCSK9 is regulated by pro-inflammatory cytokine TNF-α in a SOCS3-dependent manner (Ruscica et al., JBC, 2016). Thus, the present work aimed to further extend this observation and studied the possible molecular mechanisms linking the effects of cytokines (TNF-α) and adipokines (leptin and resistin) on de novo lipogenesis and PCSK9 expression. Methods: Human hepatocellular liver carcinoma cell line (HepG2) and HepG2 overexpressing PCSK9 (HepG2PCSK9) were used as in vitro tools. qPCR, Western blot, ELISA and luciferase reporter assays, together with siRNA directed to STAT3 and SOCS3, were used. Results: HepG2 expresses leptin (ObRl), resistin (Adenylyl cyclase-associated protein 1, CAP1), and adiponectin (AdipoR2) receptors. Notably, HepG2PCSK9 expresses higher levels of ObRl and AdipoR2. Twenty-four h treatment of HepG2 with TNF-α (10 ng/mL), leptin (200 ng/mL) and resistin (50 ng/mL) induced the expression of both PCSK9 (2.3-, 2.0- and 3.5-fold, respectively) and the suppressor of JAK/STAT pathway, SOCS3 (3-, 1.8- and 1.9-fold, respectively). TNF-α and leptin increased the secreting PCSK9 (+15% and +20%, respectively) but only leptin stimulated (+46%) PCSK9 promoter activity (+20%). TNF-α, leptin and resistin induced the gene expression of apoB, sterol regulatory element-binding protein 1 (SREBP1), stearoyl-CoA desaturase-1 (SCD-1), fatty acid synthase (FAS) and microsomal triglyceride transfer protein (MTP). The TNF-α mediated effects were inhibited by transfection with siRNA anti-STAT3, suggesting the involvement of the JAK/STAT pathway. Conclusions: Pro-inflammatory cytokines and adipokines up-regulate PCSK9 expression and the key genes involved in the de novo lipogenesis. Future analyses will investigate the potential role of JAK/STAT/SOCS3 pathways in mediating these effects.
PCSK9 expression is regulated by pro-inflammatory cytokines and adipokines in HEPG2 cells / M. Botta, C. Songia, C. Macchi, N. Ferri, A. Corsini, P. Magni, M. Ruscica. ((Intervento presentato al 39. convegno European Lipoprotein Club Meeting tenutosi a Tutzing nel 2016.
|Titolo:||PCSK9 expression is regulated by pro-inflammatory cytokines and adipokines in HEPG2 cells|
MAGNI, PAOLO (Penultimo)
RUSCICA, MASSIMILIANO (Ultimo)
|Data di pubblicazione:||8-set-2016|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
Settore MED/05 - Patologia Clinica
Settore BIO/14 - Farmacologia
|Citazione:||PCSK9 expression is regulated by pro-inflammatory cytokines and adipokines in HEPG2 cells / M. Botta, C. Songia, C. Macchi, N. Ferri, A. Corsini, P. Magni, M. Ruscica. ((Intervento presentato al 39. convegno European Lipoprotein Club Meeting tenutosi a Tutzing nel 2016.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|