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Soluble LDL-receptor is induced by TNF-α and inhibits hepatocytic clearance of LDL-cholesterol
Abstract
Defective LDL-C clearance and hence its elevation in the circulation is an established risk factor for cardiovascular diseases (CVDs) such as myocardial infarction (MI). A soluble LDL-receptor (sLDL-R) has been detected in human plasma which correlates strongly with circulating LDL-C and classical conditions that promote chronic inflammation. However, the mechanistic interplay between sLDL-R, inflammation, and CVDs remains to be investigated. Here, we report that stimulation of HepG2 cells with TNF-α induces the release of sLDL-R into culture supernatants. In addition, TNF-α induces gene expression of peptidases ADAM-17 and MMP-14 in HepG2 cells, and inhibiting these peptidases using TMI 1 significantly reduces the TNF-α induced sLDL-R release. We found that a soluble form of recombinant LDL-R (100 nM) can strongly bind to LDL-C and form a stable complex (KD = E-12). Moreover, incubation of HepG2 cells with this recombinant LDL-R resulted in reduced LDL-C uptake in a dose-dependent manner. In a nested case-control study, we found that baseline sLDL-R in plasma is positively correlated with plasma total cholesterol level. Furthermore, a twofold increase in plasma sLDL-R was associated with a 55% increase in the risk of future MI [AOR = 1.55 (95% CI = 1.10–2.18)]. Nevertheless, mediation analyses revealed that a significant proportion of the association is mediated by elevation in plasma cholesterol level (indirect effect β = 0.21 (95% CI = 0.07–0.38). Collectively, our study shows that sLDL-R is induced by a pro-inflammatory cytokine TNF-α via membrane shedding. Furthermore, an increase in sLDL-R could inhibit hepatic clearance of LDL-C increasing its half-life in the circulation and contributing to the pathogenesis of MI. Key messages: TNF-α causes shedding of hepatocytic LDL-R through induction of ADAM-17 and MMP-14. sLDL-R binds strongly to LDL-C and inhibits its uptake by hepatocytic cells. Plasma sLDL-R is positively correlated with TNF-α and cholesterol. Plasma sLDL-R is an independent predictor of myocardial infarction (MI). Plasma cholesterol mediates the association between sLDL-R and MI.
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MT1-MMP is regulated by TNFα, and in HepG2 cells treated with TNFα, the release of sLDLR is increased.
“A study by Zegeye et al. found that MT1-MMP is regulated by TNFα [102].Accordingly, in HepG2 cells treated with TNFα, the release of sLDLR is increased.”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [102]
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Sorted by citations
The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms
Ndoj, K., Meurs, A., Papaioannou, D., Bjune, K., & Zelcer, N. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2024.119082 · Cited by 17
Metadata
- Authors
- Zegeye, M. M., Nakka, S. S., Andersson, J. S. O., Söderberg, S., Ljungberg, L. U., Kumawat, A. K., & Sirsjö, A.
- ORCID
- Zegeye, Mulugeta M.
- Venue
- Journal of Molecular Medicine
- Published
- 2023-10-20
- Volume
- 101
- Issue
- 12
- Pages
- 1615-1626
- ISSN
- 0946-2716
- 1432-1440
- PMC
- PMC10697900
- Cited by
- 20
- References
- 5
- Language
- en
- Funders
- Stiftelsen för Kunskaps- och Kompetensutveckling (Dnr 2018-0035, Dnr 2021-0038)
- Örebro University
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