The enigma of soluble LDLR: could inflammation be the key?

Mbikay, Majambu; Mayne, Janice; Chrétien, Michel

doi:10.1186/s12944-020-1199-9

Cited by 12 publications

(12 citation statements)

References 26 publications

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“…LDLR most investigated role is in the clearance of atherogenic Low Density Lipoproteins particles. However, LDLR can also be detected in circulation after cleavage by ADAM-17, an enzyme activated by inflammation (Mbikay et al, 2020).…”

Section: Igfbp2/ Insulin Like Growth Factormentioning

confidence: 99%

Mechanism-Based Biomarker Prediction for Low-Grade Inflammation in Liver and Adipose Tissue

et al. 2021

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Metabolic disorders, such as obesity and type 2 diabetes have a large impact on global health, especially in industrialized countries. Tissue-specific chronic low-grade inflammation is a key contributor to complications in metabolic disorders. To support therapeutic approaches to these complications, it is crucial to gain a deeper understanding of the inflammatory dynamics and to monitor them on the individual level. To this end, blood-based biomarkers reflecting the tissue-specific inflammatory dynamics would be of great value. Here, we describe an in silico approach to select candidate biomarkers for tissue-specific inflammation by using a priori mechanistic knowledge from pathways and tissue-derived molecules. The workflow resulted in a list of candidate markers, in part consisting of literature confirmed biomarkers as well as a set of novel, more innovative biomarkers that reflect inflammation in the liver and adipose tissue. The first step of biomarker verification was on murine tissue gene-level by inducing hepatic inflammation and adipose tissue inflammation through a high-fat diet. Our data showed that in silico predicted hepatic markers had a strong correlation to hepatic inflammation in the absence of a relation to adipose tissue inflammation, while others had a strong correlation to adipose tissue inflammation in the absence of a relation to liver inflammation. Secondly, we evaluated the human translational value by performing a curation step in the literature using studies that describe the regulation of the markers in human, which identified 9 hepatic (such as Serum Amyloid A, Haptoglobin, and Interleukin 18 Binding Protein) and 2 adipose (Resistin and MMP-9) inflammatory biomarkers at the highest level of confirmation. Here, we identified and pre-clinically verified a set of in silico predicted biomarkers for liver and adipose tissue inflammation which can be of great value to study future development of therapeutic/lifestyle interventions to combat metabolic inflammatory complications.

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Section: Igfbp2/ Insulin Like Growth Factormentioning

confidence: 99%

Mechanism-Based Biomarker Prediction for Low-Grade Inflammation in Liver and Adipose Tissue

et al. 2021

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“…We chose this derivative because it is the most abundant flavonol in the plant kingdom, and because comparative pharmacokinetic studies have indicated that it is more bioavailable than the aglycone form . In particular, we wanted to understand how Q3G regulates the expression of proprotein convertase subtilisin/kexin‐type 9 (PCSK9), an endoproteinase which, once secreted, turns into an escort protein for the LDL receptor (LDLR), directing it from the plasma membrane toward lysosomes for degradation . LDLR mediates the uptake of circulating LDL‐cholesterol (LDL‐C) into cells; by degrading the receptor, PCSK9 opposes this uptake.…”

Section: Introductionmentioning

confidence: 99%

Mice Fed a High‐Cholesterol Diet Supplemented with Quercetin‐3‐Glucoside Show Attenuated Hyperlipidemia and Hyperinsulinemia Associated with Differential Regulation of PCSK9 and LDLR in their Liver and Pancreas

Mbikay

Mayne

Sirois

et al. 2018

Molecular Nutrition Food Res

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“…The absence of difference at the levels of PCSK9 in our case with a parallel increase of the levels of circulating LDLR, may indeed be associated with increased LDLR shedding in the presence of RA. Increased inflammation, such as that under RA conditions, may be the key factor via activation of sheddases, mostly those of the ADAM family, such as ADAM-17 (32). Further prospective studies specifically examining soluble LDLR are needed to elucidate the underlying mechanisms and pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

PCSK9/LDLR System and Rheumatoid Arthritis-Related Atherosclerosis

Arida

Legaki

Kravvariti

et al. 2021

Front. Cardiovasc. Med.

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Background/Aims: Rheumatoid arthritis (RA) is associated with the emergence of cardiovascular disease, while chronic inflammation is considered a common denominator for their parallel progression. The Proprotein convertase subtilisin/kexin type 9 (PCSK9)/LDL-Receptor (LDLR) system is of high importance during atherogenesis, via regulating the clearance of LDL from the circulation; nevertheless the role of this molecular mechanism during RA-related atheromatosis is not known.Methods: Herein, high-resolution ultrasound measurements for arterial hypertrophy, atheromatosis and arterial stiffness as well as comprehensive biochemical profiling were performed in 85 RA patients. The circulating levels of PCSK9 and LDLR were measured and their potential associations as well as of the PCSK9/LDLR ratio with patients' characteristics and the degree of atherosclerosis were investigated.Results: Increased LDLR levels and decreased PCSK9/LDLR ratio were found in RA patients with at least 2 atheromatic plaques as compared to the ones without any plaques. In addition the levels of both PCSK9 and LDLR were positively correlated with the presence of atheromatic plaques as an age- and gender- adjusted multivariate analysis revealed.Conclusions: Our data imply that the PCSK9/LDLR system plays a significant role during RA-related atherosclerosis and may therefore be used as a screening tool for disease progression in the future.

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The enigma of soluble LDLR: could inflammation be the key?

Cited by 12 publications

References 26 publications

Mechanism-Based Biomarker Prediction for Low-Grade Inflammation in Liver and Adipose Tissue

Mechanism-Based Biomarker Prediction for Low-Grade Inflammation in Liver and Adipose Tissue

Mice Fed a High‐Cholesterol Diet Supplemented with Quercetin‐3‐Glucoside Show Attenuated Hyperlipidemia and Hyperinsulinemia Associated with Differential Regulation of PCSK9 and LDLR in their Liver and Pancreas

PCSK9/LDLR System and Rheumatoid Arthritis-Related Atherosclerosis

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