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Soluble LDL-receptor is induced by TNF-α and inhibits hepatocytic clearance of LDL-cholesterol
Örebro University, School of Medical Sciences. Cardiovascular Research Centre.ORCID iD: 0000-0001-6952-8952
Department of Infectious Diseases, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
Department of Public Health and Clinical Medicine, Skellefteå Research Unit, Umeå University, 931 86, Skellefteå, Sweden.
Department of Public Health and Clinical Medicine, Medicine Unit, Umeå University, Umeå, Sweden.
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2023 (English)In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 101, no 12, p. 1615-1626Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Springer, 2023. Vol. 101, no 12, p. 1615-1626
Keywords [en]
ADAM-17, Chronic inflammation, Hypercholesterolemia, MMP-14, Mediation analyses, Myocardial infarction
National Category
Cardiology and Cardiovascular Disease
Identifiers
URN: urn:nbn:se:oru:diva-109360DOI: 10.1007/s00109-023-02379-4ISI: 001088058800001PubMedID: 37861809Scopus ID: 2-s2.0-85174533259OAI: oai:DiVA.org:oru-109360DiVA, id: diva2:1806597
Funder
Örebro UniversityKnowledge Foundation, 2018-0035 2021-0038Available from: 2023-10-23 Created: 2023-10-23 Last updated: 2025-02-10Bibliographically approved

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Zegeye, Mulugeta MLjungberg, LizaKumawat, Ashok KumarSirsjö, Allan

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