Role of Proprotein Convertase Subtilisin/Kexin Type 9 in the Pathogenesis of Graves’ Orbitopathy in Orbital Fibroblasts

Ga Eun Lee, Jinjoo Kim, Jihei Sara Lee, Jae Sang Ko, Eun Jig Lee, Jin Sook Yoon

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Background: The proprotein convertase subtilisin/kexin type 9 (PCSK9) has been implicated in the pathogenesis of inflammatory diseases. We sought to investigate the role of PCSK9 in the pathogenesis of Graves’ orbitopathy (GO) and whether it may be a legitimate target for treatment. Methods: The PCSK9 was compared between GO (n=11) and normal subjects (n=7) in orbital tissue explants using quantitative real-time PCR, and in cultured interleukin-1β (IL-1β)-treated fibroblasts using western blot. Western blot was used to identify the effects of PCSK9 inhibition on IL-1β-induced pro-inflammatory cytokines production and signaling molecules expression as well as levels of adipogenic markers and oxidative stress-related proteins. Adipogenic differentiation was identified using Oil Red O staining. The plasma PCSK9 concentrations were compared between patients with GO (n=44) and healthy subjects (n=26) by ELISA. Results: The PCSK9 transcript level was higher in GO tissues. The depletion of PCSK9 blunted IL-1β-induced expression of intercellular adhesion molecule 1 (ICAM-1), IL-6, IL-8, and cyclooxygenase-2 (COX-2) in GO and non-GO fibroblasts. The levels of activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and phosphorylated forms of Akt and p38 were diminished when PCSK9 was suppressed in GO fibroblasts. Decreases in lipid droplets and attenuated levels of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein β (C/EBPβ), and leptin as well as hypoxia-inducible factor 1α (HIF-1α), manganese superoxide dismutase (MnSOD), thioredoxin (Trx), and heme oxygenase-1 (HO-1) were noted when PCSK9 was suppressed during adipocyte differentiation. The plasma PCSK9 level was significantly higher in GO patients and correlated with level of thyrotropin binding inhibitory immunoglobulin (TBII) and the clinical activity score (CAS). Conclusions: PCSK9 plays a significant role in GO. The PCSK9 inhibition attenuated the pro-inflammatory cytokines production, oxidative stress, and fibroblast differentiation into adipocytes. PCSK9 may serve as a therapeutic target and biomarker for GO.

Original languageEnglish
Article number607144
JournalFrontiers in Endocrinology
Publication statusPublished - 2021 Jan 8

Bibliographical note

Funding Information:
This study was supported by a faculty research grant of Yonsei University College of Medicine (6-2020-0093).

Publisher Copyright:
© Copyright © 2021 Lee, Kim, Lee, Ko, Lee and Yoon.

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism


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