STAT3 inhibition induces PCSK9 in hepatic cell line: possible involvement in hypertriglyceridemia associated with insulin resistance
Poster
Data di Pubblicazione:
2015
Citazione:
STAT3 inhibition induces PCSK9 in hepatic cell line: possible involvement in hypertriglyceridemia associated with insulin resistance / C. Ricci, M. Ruscica, C. Macchi, P. Magni, A. Corsini, N. Ferri. - In: ATHEROSCLEROSIS. - ISSN 0021-9150. - 241:1(2015 Jul), pp. e46-e47. (Intervento presentato al 83. convegno European Association of Atherosclerosis tenutosi a Glasgow nel 2015) [10.1016/j.atherosclerosis.2015.04.167].
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
PCSK9 regulates the circulating LDL-cholesterol levels by inducing LDLR
degradation. However, PCSK9 levels are positively correlated with insulin
resistance, liver steatosis and plasma VLDL-TG concentrations. This
evidence suggests that PCSK9 could 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 cells. Forced
overexpression of SOCS3 determined the 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 an increase of PCSK9 mRNA
(7.82±1.73 fold) and protein (2.18±1.13 fold) without significant changes
of HMG-CoA reductase, LDLR and 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 fattyacid
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
Elenco autori:
C. Ricci, M. Ruscica, C. Macchi, P. Magni, A. Corsini, N. Ferri
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