PCSK9 plays a significant role in cholesterol homeostasis and lipid transport in intestinal epithelial cells

Lévy, Émile; Ouadda, Ali Ben Djoudi; Spahis, Schohraya; Sané, Alain Théophile; Garofalo, Carole; Grenier, Emilie; Emonnot, Lea; Yara, Sabrina; Couture, Patrick; Beaulieu, Jean‐François; Ménard, Daniel; Seidah, Nabil G.; Elchebly, Mounib

doi:10.1016/j.atherosclerosis.2013.01.023

Cited by 124 publications

(130 citation statements)

References 38 publications

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“…12 PCSK9 regulation of the LDLR protein levels in intestinal cell lines has been reported. 69,115 The possible implication of PCSK9 in the transintestinal reverse cholesterol excretion from the small intestine has been recently evoked. 116 Although the LDLR is involved in this process, it seems that yet another receptor(s) sensitive to PCSK9 is/are also implicated.…”

Section: Small Intestine and Pancreasmentioning

confidence: 99%

“…68 Recently, we showed that PCSK9 can enhance the degradation of LRP1 in various cells 44 although proof of this activity in vivo is still lacking. Finally, CD36, a scavenger receptor with multiple ligands and cellular functions, including facilitating cellular uptake of free fatty acids (FFA), was also suspected to be a PCSK9 target in intestinal epithelial cells 69 and adipose tissue. 65 Recently, this PCSK9 activity on CD36 was elegantly proven in cells and adipocytes.…”

Section: Other Pcsk9 Target Proteinsmentioning

confidence: 99%

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Pcsk9

Seidah

Awan

Chrétien³

et al. 2014

Circulation Research

Self Cite

502

197

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Section: Small Intestine and Pancreasmentioning

confidence: 99%

Section: Other Pcsk9 Target Proteinsmentioning

confidence: 99%

Pcsk9

Seidah

Awan

Chrétien³

et al. 2014

Circulation Research

Self Cite

502

197

View full text Add to dashboard Cite

“…It seems that other receptors, including known PCSK9 targets, such as very low-density lipoprotein receptor (VLDLR) 28) , apoE receptor 2 28) , lipoprotein receptor-related protein 1 29,30) , cluster of differentiation 36 (CD36) 30) , or a yet unknown receptor, are also sensitive to PCSK9. Studies on PCSK9-knockout and PCSK9-transgenic mice reveal that PCSK9 downregulates the entry of triglycerides (TG) and free-fatty acids (FFAs) into visceral adipocytes possibly via adipose tissue VLDLR and CD36 degradation, resulting in decreased postprandial hypertriglyceridemia and enhanced chylomicron clearance 31) .…”

Section: Main Pathogenic Hypothesis Of Atherosclerosismentioning

confidence: 99%

“…PCSK9 has also been detected in the endocrine pancreas and more specifically in pancreatic cells 44) . PCSK9 alters endocrine pancreatic function in mice, and PCSK9 deficiency is associated with morphological abnormalities in islets, resulting in decreased insulin secretion and human intestinal epithelial cells with recombinant PCSK9 enhances cholesterol uptake, suggesting a role for PCSK9 in lipid absorption 30) . These effects of PCSK9 on lipid biomarkers suggest that PCSK9 is essential in lipid metabolism beyond LDL-C level regulation.…”

Section: Pcsk9 and Cardiometabolic Risk Factorsmentioning

confidence: 99%

PCSK9: A key factor modulating atherosclerosis

2015

J Atheroscler Thromb

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Coronary artery disease (CAD) due to obstructive atherosclerosis is a leading cause of death and has been recognized as a worldwide health threat. Measures to decrease low-density lipoprotein cholesterol (LDL-C) levels are the cornerstone in the management of patients with atherosclerotic cardiovascular disease, particularly those with CAD, for over two decades. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a newly recognized protein, plays a key role in cholesterol homeostasis by enhancing degradation of hepatic LDL receptor (LDLR). Interestingly, PCSK9 is also involved in the inflammatory process. Plasma PCSK9 and lipid or nonlipid cardiovascular risk factors are correlated, and the associations between PCSK9 with cardiovascular health and disease make this protein worthy of attention for the treatment of hyperlipidemia and atherosclerosis. Here, we provide an overview of the physiological role of PCSK9, which contributes to atherosclerosis, and provide data on PCSK9 as a novel pharmacological target. Clinical evidence shows that PCSK9 inhibition is as promising as statins as a target to treat CAD. The efficacy of these drugs may potentially enable effective CAD prophylaxis for more patients.

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“…Enterocytes express the LDL receptor on their basolateral surface and PCSK9 can possibly activate their degradation, modulating metabolism of cholesterol and chylomicrons. 25 Some recent studies suggest a possible role of PCSK9 expressed in the kidney in modulating absorption of sodium by degradation of the Notes: PCSK9 regulates LDL-R expression. Circulating PCSK9 protein binds to the LDL-R. Once internalized into the liver cell, the PCSK9 protein directs the LDL-R to the lysosome for degradation.…”

Section: Introductionmentioning

confidence: 99%

Potential of PCSK9 as a new target for the management of LDL cholesterol

Mombelli¹,

Castelnuovo²,

Pavanello³

2015

RRCC

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A large proportion of patients at high risk for cardiovascular disease continue to suffer from cardiovascular events despite current therapies. The need for additional therapies to lower the residual risk has led to research on new pharmacological approaches. The discovery of proteins regulating the activity of the low-density lipoprotein receptor has been a major breakthrough in the development of new cholesterol-lowering drugs. This review describes inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a promising treatment for familial hypercholesterolemia, especially the relatively good short-term safety of PCSK9 inhibitors. In particular, we focus on its additive effect with statins and its advantage as a monotherapy in statin-intolerant patients. The additional low-density lipoprotein cholesterol lowering obtained with PCSK9 inhibition will be able to reduce the additional risk, but its effect on cardiovascular events has to be evaluated in future studies.

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PCSK9 plays a significant role in cholesterol homeostasis and lipid transport in intestinal epithelial cells

Cited by 124 publications

References 38 publications

Pcsk9

Pcsk9

PCSK9: A key factor modulating atherosclerosis

Potential of PCSK9 as a new target for the management of LDL cholesterol

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