STAT3 inhibition induces PCSK9 in hepatic cell line: possible involvement in hypertriglyceridemia associated with insulin resistance

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