Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9: The Role of STAT3

Chiara Macchi, Maria Francesca Greco, Margherita Botta, Paola Sperandeo, Paola Dongiovanni, Luca Valenti, Arrigo F.G. Cicero, Claudio Borghi, Maria Giovanna Lupo, Stefano Romeo, Alberto Corsini, Paolo Magni, Nicola Ferri, Massimiliano Ruscica

Research output: Contribution to journalArticlepeer-review

Abstract

In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokine 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 STAT3. In HepG2 cells, leptin and resistin up-regulated 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 knockdown of STAT3 did not affect the expression of leptin and resistin receptors or that of PCSK9. The analysis of the human PCSK9 promoter region showed that the two adipokines raised PCSK9 promoter activity via the involvement of a sterol regulatory element motif. In healthy males, a positive association between circulating leptin and PCSK9 levels was found only when the body mass index was <25 kg/m2. In conclusion, this study identified STAT3 as one of the molecular regulators of leptin- and resistin-mediated transcriptional induction of PCSK9.

Original languageEnglish
Pages (from-to)2226-2236
Number of pages11
JournalAmerican Journal of Pathology
Volume190
Issue number11
DOIs
Publication statusPublished - Nov 2020

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Fingerprint Dive into the research topics of 'Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9: The Role of STAT3'. Together they form a unique fingerprint.

Cite this