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

C. Macchi, M.F. Greco, M. Botta, P. Sperandeo, P. Dongiovanni, L. Valenti, A.F.G. Cicero, C. Borghi, M.G. Lupo, S. Romeo, A. Corsini, P. Magni, N. Ferri, M. 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. © 2020 American Society for Investigative Pathology
Original languageEnglish
Pages (from-to)2226-2236
Number of pages11
JournalAm. J. Pathol.
Volume190
Issue number11
DOIs
Publication statusPublished - 2020

Keywords

  • leptin
  • low density lipoprotein
  • proprotein convertase 9
  • resistin
  • STAT3 protein
  • LEP protein, human
  • PCSK9 protein, human
  • RETN protein, human
  • STAT3 protein, human
  • adult
  • Article
  • body mass
  • cohort analysis
  • controlled study
  • enzyme activation
  • evaluation study
  • female
  • gene expression regulation
  • gene knockdown
  • gene silencing
  • Hep-G2 cell line
  • human
  • human cell
  • human tissue
  • inflammation
  • lipoprotein metabolism
  • male
  • middle aged
  • PCSK9 gene
  • priority journal
  • promoter region
  • protein expression
  • protein motif
  • protein phosphorylation
  • signal transduction
  • upregulation
  • atherosclerosis
  • biosynthesis
  • DNA responsive element
  • genetics
  • metabolism
  • obesity
  • pathology
  • Atherosclerosis
  • Gene Expression Regulation, Enzymologic
  • Hep G2 Cells
  • Humans
  • Leptin
  • Obesity
  • Proprotein Convertase 9
  • Resistin
  • Response Elements
  • STAT3 Transcription Factor
  • Up-Regulation

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