PCSK9 and LDLR degradation

Lagace, Thomas A.

doi:10.1097/mol.0000000000000114

Cited by 290 publications

(151 citation statements)

References 65 publications

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“…Paradoxically, these two genes would be expected to oppose one another, as LXR-induced expression of RP1-13D10.2 would increase LDLR activity, while LXR-induced expression of MYLIP would stimulate LDLR decay. However, this is similar to the well-known phenomena in which SREBF2 both induces LDLR transcription, while stimulating expression of a factor, PCSK9, that promotes LDLR protein decay 31 .…”

Section: Discussionsupporting

confidence: 67%

RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol

Mitchel¹,

Theusch²,

Cubitt³

et al. 2016

Circ Cardiovasc Genet

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Background Numerous genetic contributors to cardiovascular disease risk have been identified through genome-wide association studies (GWAS); however, identifying the molecular mechanism underlying these associations is not straightforward. The JUPITER trial of rosuvastatin users identified a sub-genome wide association of rs6924995, a SNP ~10kb downstream of MYLIP (aka IDOL, inducible degrader of LDLR), with LDL cholesterol statin response. Interestingly, though this signal was initially attributed to MYLIP, rs6924995 lies within RP1-13D10.2, an uncharacterized long noncoding RNA. Methods and Results Using simvastatin and sham incubated lymphoblastoid cell lines from participants of the Cholesterol and Pharmacogenetics simvastatin clinical trial, we found that statin induced change in RP1-13D10.2 levels differed between cell lines from the tails of the Caucasian and African American LDLC response distributions, while no difference in MYLIP was observed. RP1-13D10.2 overexpression in Huh7 and HepG2 increased LDLR transcript levels, increased LDL uptake, and decreased media levels of APOB. In addition, we found a trend of slight differences in the effects of RP1-13D10.2 overexpression on LDLR transcript levels between hepatoma cells transfected with the rs6924995 “A” vs. “G” allele, and a suggestion of an association between rs6924995 and RP1-10D13.2 expression levels in the CAP LCLs. Lastly, RP1-13D10.2 expression levels appear to be sterol regulated, consistent with its potential role as a novel lipid regulator. Conclusions RP1-13D10.2 is a long noncoding RNA that regulates LDLR and may contribute to LDLC response to statin treatment. These findings highlight the potential role of non-coding RNAs as determinants of inter-individual variation in drug response.

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Section: Discussionsupporting

confidence: 67%

RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol

Mitchel¹,

Theusch²,

Cubitt³

et al. 2016

Circ Cardiovasc Genet

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“…The function of PCSK9 is the binding of specific cell surface receptors to escort them towards intracellular acidic endosome/lysosome degradation compartments 58, 59. Specifically, PCSK9 plays a key role in the regulation of hepatic LDLR function through receptor binding and targeting to intracellular lysosomal degradation 19; this leads to reduced LDLR recycling and expression on the cell membrane, decreased plasma LDL catabolism and increased plasma LDL‐C levels.…”

Section: Pcsk9 and Lipoprotein Receptorsmentioning

confidence: 99%

“…Specifically, a concentration‐dependent impact of PCSK9 on liver cell CD81 expression has been documented 16, 17. Also, circulating PCSK9 down‐regulates LDLR expression on the hepatocyte surface, thus decreasing LDL catabolism and increasing plasma LDL‐cholesterol (LDL‐C) levels 18, 19. Although there is evidence that PCSK9 decreases VLDLR expression in adipose tissue 20, whether such a down‐regulation may occur in the liver is not established and the potential impact of PCSK9‐mediated change in VLDLR expression on HCV infection is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus and proprotein convertase subtilisin/kexin type 9: a detrimental interaction to increase viral infectivity and disrupt lipid metabolism

Pirro

Bianconi

Francisci

et al. 2017

J Cellular Molecular Medi

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From viral binding to the hepatocyte surface to extracellular virion release, the replication cycle of the hepatitis C virus (HCV) intersects at various levels with lipid metabolism; this leads to a derangement of the lipid profile and to increased viral infectivity. Accumulating evidence supports the crucial regulatory role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipoprotein metabolism. Notably, a complex interaction between HCV and PCSK9 has been documented. Indeed, either increased or reduced circulating PCSK9 levels have been observed in HCV patients; this discrepancy might be related to several confounders, including HCV genotype, human immunodeficiency virus (HIV) coinfection and the ambiguous HCV‐mediated influence on PCSK9 transcription factors. On the other hand, PCSK9 may itself influence HCV infectivity, inasmuch as the expression of different hepatocyte surface entry proteins and receptors is regulated by PCSK9. The aim of this review is to summarize the current evidence about the complex interaction between HCV and liver lipoprotein metabolism, with a specific focus on PCSK9. The underlying assumption of this review is that the interconnections between HCV and PCSK9 may be central to explain viral infectivity.

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“…The first, PCSK9 can bind to LDLR right after synthesis and direct to lysosomal vesicles [34]. In the second route, surrounding PCSK9 binds to low-density lipoprotein (LDLR) receptors present on the surface of hepatocytes, causing their internalization and degradation within lysosomal vesicles [33]. This affects availability of LDLR on the cell surface and consequently concentration of LDL in plasma [31,[35][36].…”

Section: Uptake Of Ldl (Low-density Lipoprotein)mentioning

confidence: 99%

“…PCSK9 is synthesized as a soluble zymogen (proPCSK9) and requires autocatalysis for its activation and maturation [33]. Once activated, PCSK9 can follow two pathways for the degradation of LDLR.…”

Section: Uptake Of Ldl (Low-density Lipoprotein)mentioning

confidence: 99%

Profile of Surrounding MicroRNAs in Low Density Lipoprotein Uptake

Mes¹,

Rsdo²,

Ea³

et al. 2017

Preprint

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Abstract:The atherosclerosis, a chronic and inflammatory disease that occurs when there are high levels of low-density lipoprotein (LDL) on plasma. This important risk factor for development of cardiovascular disease (CVD) is the main cause of death worldwide. MicroRNAs have recently emerged as potential biomarkers and therapeutic target for lipid metabolism disorders. In this review, we will provide profile of surrounding miRNAs that have demonstrated being regulators of PCSK9, LDLR and APOB100 genes. Recent work has identified the mir-148, mir-128, mir-27a/b, mir-185, mir-301, mir-130 as important regulators of this pathway because they decrease supply of LDL receptors through interaction with PCSK9. Inhibition of LDLR expression cause elevation of plasma LDL levels which induces atherosclerosis. While mir-30c, mir-122, mir-34 decrease MTTP, which promotes degradation of APOB100 preventing assembly and secretion of VLDL. We conclude that, when overexpressed, mir-148a, mir128 and mir-27a/b, mir-122 and mir-34 are related to decrease in LDLR, facilitating occurrence of atherosclerosis. While mir-30 has been linked to decreased atherosclerosis. Detection of miRNAs profile could be used in the future as a biomarker for disturbs linked to c-LDL uptake and in future anti-miRNAs therapies may be used in the treatment of atherosclerosis.

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PCSK9 and LDLR degradation

Cited by 290 publications

References 65 publications

RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol

RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol

Hepatitis C virus and proprotein convertase subtilisin/kexin type 9: a detrimental interaction to increase viral infectivity and disrupt lipid metabolism

Profile of Surrounding MicroRNAs in Low Density Lipoprotein Uptake

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