Proprotein Convertase Subtilisin/Kexin Type 9

Macchi, Chiara; Ferri, Nicola; Sirtori, Cesare R.; Corsini, Alberto; Banach, Maciej; Ruscica, Massimiliano

doi:10.1016/j.ajpath.2021.04.016

Cited by 81 publications

(65 citation statements)

References 114 publications

(136 reference statements)

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“…In humans, circulating PCSK9 is associated with intermediate density lipoproteins [35], and high PCSK9 plasma concentrations may associate with increased risk of T2D development [18]. Although, it was recently found that PCSK9 inhibition does not appear to significantly impact on insulin secretion in mice and humans [51,52], two other studies suggested that human PCSK9 loss-of-function variants were associated with a raised risk to develop new-onset diabetes whereas PCSK9 may mediate 11% of insulin resistance in obese and depressed patients [53,54]. Thus, the mechanisms responsible for the association of specific TRL and LDL particle characteristics with T2D development are still unprecisely known and should await further studies.…”

Section: Discussionmentioning

confidence: 99%

Triglyceride-rich lipoprotein and LDL particle subfractions and their association with incident type 2 diabetes: the PREVEND study

Sokooti

Flores‐Guerrero

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et al. 2021

Cardiovasc Diabetol

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Background Triglyceride-rich lipoproteins particles (TRLP) and low density lipoprotein particles (LDLP) vary in size. Their association with β-cell function is not well described. We determined associations of TRLP and LDLP subfractions with β-cell function, estimated as HOMA-β, and evaluated their associations with incident T2D in the general population. Methods We included 4818 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study without T2D at baseline. TRLP and LDLP subfraction concentrations and their average sizes were measured using the LP4 algorithm of the Vantera nuclear magnetic resonance platform. HOMA-IR was used as measure of insulin resistance. HOMA-β was used as a proxy of β-cell function. Results In subjects without T2D at baseline, very large TRLP, and LDL size were inversely associated with HOMA-β, whereas large TRLP were positively associated with HOMA-β when taking account of HOMA-IR. During a median follow-up of 7.3 years, 263 participants developed T2D. In multivariable-adjusted Cox regression models, higher concentrations of total, very large, large, and very small TRLP (reflecting remnants lipoproteins) and greater TRL size were associated with an increased T2D risk after adjustment for relevant covariates, including age, sex, BMI, HDL-C, HOMA-β, and HOMA-IR. On the contrary, higher concentrations of large LDLP and greater LDL size were associated with a lower risk of developing T2D. Conclusions Specific TRL and LDL particle characteristics are associated with β-cell function taking account of HOMA-IR. Moreover, TRL and LDL particle characteristics are differently associated with incident T2D, even when taking account of HOMA-β and HOMA-IR.

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Section: Discussionmentioning

confidence: 99%

Triglyceride-rich lipoprotein and LDL particle subfractions and their association with incident type 2 diabetes: the PREVEND study

Sokooti

Flores‐Guerrero

Heerspink

et al. 2021

Cardiovasc Diabetol

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“…It was established that PCSK9 can stimulate the degradation of LDLR which is essential for tumorigenesis [ 33 , 34 ]. The roles of PCSK9 in cancer have been highlighted recently in terms of regulation of inflammation via SOCS3-STAT3 pathway [35] and cell proliferation and apoptosis [36] . Moreover, the deficiency of PCSK9 was shown to prevent tumor growth in a manner that depends on cytotoxic T cells that further implicated applications in cancer immunotherapy [37] .…”

Section: Discussionmentioning

confidence: 99%

Proprotein convertase subtilisin/kexin Type 9 is required for Ahnak-mediated metastasis of melanoma into lung epithelial cells

et al. 2021

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Highlights Ahnak −/− mice were more resistant to the pulmonary metastasis of B16F10 cells. Transcriptomic analyses revealed that PCSK9 was a candidate for lung metastasis. The lung metastasis was suppressed in Scgb1a1-Cre/PCSK9 fl/fl mice. Ahnak-TGFβ-PCSK9 axis regulates pulmonary metastasis of B16F10 cells.

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“…It is positively associated with albumin, liver enzymes (ALT, ALP, AST, GGT) and with hepatic steatosis, although whether this association is confounded by or mediated by LDL-C is still unclear (Paquette et al, 2020). Finally, PCSK9 is also expressed in the intestine, endocrine pancreas and brain, and non-lipid-lowering effects of PCSK9 inhibition could also be linked to platelet activation (Qi et al, 2021), cell proliferation and apoptosis (Macchi et al, 2021). Importantly, there is great interindividual variation in both PCSK9 levels and response to PCSK9 inhibitors (Chasman et al, 2012;Qamar et al, 2019;Ramin-Mangata et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study

et al. 2021

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Pharmacological inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is an established therapeutic option to treat hypercholesterolemia, and plasma PCSK9 levels have been implicated in cardiovascular disease incidence. A number of genetic variants within the PCSK9 gene locus have been shown to modulate PCSK9 levels, but these only explain a very small percentage of the overall PCSK9 interindividual variation. Here we present data on the genetic association structure between PCSK9 levels and genom-wide genetic variation in a healthy sample from the general population. We performed a genome-wide association study of plasma PCSK9 levels in a sample of Brazilian individuals enrolled in the Estudo Longitudinal de Saude do Adulto cohort (n=810). Enrolled individuals were free from cardiovascular disease, diabetes and were not under lipid-lowering medication. Genome-wide genotyping was conducted using the Axiom_PMRA.r3 array, and imputation was performed using the TOPMED multi-ancestry sample panel as reference. Total PCSK9 plasma concentrations were determined using the Quantikine SPC900 ELISA kit. We observed two genome-wide significant loci and seven loci that reached the pre-defined value of p threshold of 1×10−6. Significant variants were near KCNA5 and KCNA1, and LINC00353. Genetic variation at the PCSK9 locus was able to explain approximately 4% of the overall interindividual variations in PCSK9 levels. Colocalization analysis using eQTL data suggested RWDD3, ATXN7L1, KCNA1, and FAM177A1 to be potential mediators of some of the observed associations. Our results suggest that PCSK9 levels may be modulated by trans genetic variation outside of the PCSK9 gene and this may have clinical implications. Understanding both environmental and genetic predictors of PCSK9 levels may help identify new targets for cardiovascular disease treatment and contribute to a better assessment of the benefits of long-term PCSK9 inhibition.

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Proprotein Convertase Subtilisin/Kexin Type 9

Cited by 81 publications

References 114 publications

Triglyceride-rich lipoprotein and LDL particle subfractions and their association with incident type 2 diabetes: the PREVEND study

Triglyceride-rich lipoprotein and LDL particle subfractions and their association with incident type 2 diabetes: the PREVEND study

Proprotein convertase subtilisin/kexin Type 9 is required for Ahnak-mediated metastasis of melanoma into lung epithelial cells

Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study

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