PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) regulates the circulating low-density lipoprotein cholesterol (LDL) levels by inducing LDL receptor (LDLR) degradation. However, PCSK9 levels are positively correlated with insulin resistance, liver steatosis and plasma very low density lipoprotein-triglycerides (VLDL-TG) concentrations. This evidence suggests that PCSK9 could also be implicated in lipid homeostasis. Chronic inflammation, associated with elevated circulating cytokines, and hepatic overexpression of suppressor of cytokine signaling (SOCS) proteins, are major determinants of hypertriglyceridemia associated to insulin resistance. In the present study, we have investigated the role of SOCS3 in the transcriptional regulation of PCSK9 in HepG2 cell line. As expected, forced overexpression of SOCS3 determined a complete abrogation of STAT3 phosphorylation, associated to: 1) induction of fatty-acid synthase mRNA levels (3.59±0.40 fold); 2) activation of SREBP transcriptional activity (1.58±0.15 fold); 3) increase apoB production (3.47±0.09 fold). SOCS3 overexpression also determined a significant increase of PCSK9 mRNA (7.82±1.73 fold) and protein, determined by Western blot analysis and ELISA assay (2.18±1.13 fold) without significant changes of HMG-CoA reductase and LDLR levels as well as of cholesterol biosynthesis. Pharmacological inhibition of STAT3 or JAK proteins also induced PCSK9 levels by 2.06±0.75 and 3.30±0.3 fold, respectively. Interestingly, insulin significantly induced STAT3 phosphorylation, fatty-acid synthase and PCSK9 mRNA levels to a similar extent in both control and SOCS3-overexpressing cells, although the overall mRNA levels of PCSK9 and fatty-acid synthase were significantly higher in HepG2 SOCS3 cells. In conclusion, we provided evidence that biological and/or pharmacological inhibition of the JAK/STAT pathway increased PCSK9 levels, both in the absence and in the presence of insulin stimulation, a possible determinant of PCSK9 transcription in insulin resistant patients.
STAT3 inhibition induces PCSK9 in hepatic cell line: possible involvement in hypertriglyceridemia associated with insulin resistance / M. Ruscica, C. Ricci, C. Macchi, P. Magni, A. Corsini, N. Ferri. ((Intervento presentato al 28. convegno Società Italiana per lo Studio dell'Arteriosclerosi (SISA) tenutosi a Roma nel 2014.
|Titolo:||STAT3 inhibition induces PCSK9 in hepatic cell line: possible involvement in hypertriglyceridemia associated with insulin resistance|
RUSCICA, MASSIMILIANO (Primo)
RICCI, CHIARA (Secondo)
CORSINI, ALBERTO (Penultimo)
FERRI, NICOLA (Ultimo)
|Data di pubblicazione:||24-nov-2014|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
Settore MED/04 - Patologia Generale
Settore MED/05 - Patologia Clinica
|Citazione:||STAT3 inhibition induces PCSK9 in hepatic cell line: possible involvement in hypertriglyceridemia associated with insulin resistance / M. Ruscica, C. Ricci, C. Macchi, P. Magni, A. Corsini, N. Ferri. ((Intervento presentato al 28. convegno Società Italiana per lo Studio dell'Arteriosclerosi (SISA) tenutosi a Roma nel 2014.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|