ArticleJournal of molecular medicine (Berlin, Germany)2023
Soluble LDL-receptor is induced by TNF-α and inhibits hepatocytic clearance of LDL-cholesterol.
Article in Journal of molecular medicine (Berlin, Germany), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 14 citations in OpenAlex.
- Selenium-Astaxanthin Co-Supplementation Synergistically Reduces PCSK9 Expression, Upregulates LDL Receptors, and Improves lipid profile and Cardiovascular Markers in Menopausal Ovariectomized Rats by attenuating inflammation and lipid peroxidation.Biological trace element research · 2026Article
- Association of metabolic variants withThe Journal of international medical research · 2026Article
- Gender differences in the plasma profiles of proprotein convertase subtilisin/kexin-type 9 (PCSK9), soluble low-density lipoprotein receptor (sLDLR), total cholesterol, and triglycerides in patients with colorectal cancer liver metastases: diagnostic and prognostic implications.Lipids in health and disease · 2026Article
- A Mendelian randomization-based drug repurposing pipeline: application to lipid traits and coronary artery disease.medRxiv : the preprint server for health sciences · 2026Article
- IL-6 triggers lysosomal degradation of LDL-R and enhances LDL-C uptake in vascular endothelial cells via macropinocytosis.Molecular medicine (Cambridge, Mass.) · 2026Article
- Associations of plasma level of soluble LDL receptor with cardiovascular events and mortality in a large prospective cohort study.Lipids in health and disease · 2026Article
- Functional analysis from ex-vivo characterization of LDLR exon 13-15 duplication associated to familial hypercholesterolemia.Frontiers in endocrinology · 2026Article
- The Emerging Role of Interleukin-32 in HIV-Associated Cardiovascular Comorbidities: A Mini Review.International journal of general medicine · 2026Review
- Associations Between Systemic Inflammatory Markers, Metabolic Dysfunction, and Liver Fibrosis Scores in Patients with MASLD.Metabolites · 2025Article
- Genetic subtyping of obesity reveals biological insights into the uncoupling of adiposity from its cardiometabolic comorbidities.Nature medicine · 2025Article
- Article
- Correlations Between Immuno-Inflammatory Biomarkers and Hematologic Indices Stratified by Immunologic SNP Genotypes.Journal of clinical medicine · 2025Article
- ApoE Receptor-2 R952Q Variant in Macrophages Elevates Soluble LRP1 to Potentiate Hyperlipidemia and Accelerate Atherosclerosis in Mice.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
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Authors and funding
7 authors at 4 institutions in 1 country.
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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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