- Macchi, Chiara, et al.
LEPTIN, RESISTIN, AND PCSK9 - THE ROLE OF STAT3.
Ingår i: The American journal of pathology. - 1525-2191.
- In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokines levels may be detrimental for the cardiovascular system. The proinflammatory leptin and resistin adipokines have been described as possible links between obesity and atherosclerosis. The present study was aimed at evaluating whether proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein metabolism, is induced by leptin and resistin through the involvement of the inflammatory pathway of signal transducer and activator of transcript 3 (STAT3). In HepG2 cells, leptin and resistin upregulated PCSK9 gene and protein expression as well as the phosphorylation of STAT3. Upon STAT3 silencing, leptin and resistin lost their ability to activate PCSK9. The knock-down of STAT3 did not affect the expression of leptin and resistin receptors as well as that of PCSK9. The analysis of human PCSK9 promoter region showed that the two adipokines raise PCSK9 promoter activity via the involvement of sterol regulatory element motif. In healthy male, a positive association between circulating leptin and PCSK9 levels was found only when BMI was < 25 kg/m2. In conclusion, our study identified STAT3 as one of the molecular regulators of leptin- and resistin-mediated transcriptional induction of PCSK9.