Proprotein convertase PCSK9 affects expression of key surface proteins in human pancreatic beta cells via intracellular and extracellular regulatory circuits

Saitoski, Kevin; Ryaboshapkina, Maria; Hamza, Ghaith M.; Jarnuczak, Andrew F.; Berthault, Claire; Carlotti, Françoise; Armanet, Mathieu; Sengupta, Kaushik; Underwood, Christina Rye; Andersson, Shalini; Guillas, Isabelle; Goff, Wilfried Le; Scharfmann, Raphaël

doi:10.1016/j.jbc.2022.102096

Cited by 7 publications

(9 citation statements)

References 60 publications

(106 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is relevant to the overall situation in obesity, as in particular, the increase in visceral adipose tissue is closely associated with lowgrade inflammation and insulin resistance in mice and patients [39]. A negative regulation of CD36 and VLDL by PCSK9 has also been shown in human pancreatic EndoC-βH1 β-cells [40]. PCSK9 is expressed in human pancreatic β-cells [41,42], suggesting that combined limitation of cholesterol, FFA and triglyceride import compensates for the low antioxidant capacity of β-cells and their sensitivity to ROS generation during increased lipid oxidation [6,7].…”

Section: Expression In Extrahepatic Tissuesmentioning

confidence: 90%

PCSK9 inhibition and cholesterol homeostasis in insulin producing β-cells

et al. 2022

View full text Add to dashboard Cite

Low-density lipoprotein cholesterol (LDL-C) plays a central role in the pathology of atherosclerotic cardiovascular disease. For decades, the gold standard for LDL-C lowering have been statins, although these drugs carry a moderate risk for the development of new-onset diabetes. The inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) have emerged in the last years as potential alternatives to statins due to their high efficiency and safety without indications for a diabetes risk so far. Both approaches finally eliminate LDL-C from bloodstream by upregulation of LDL receptor surface expression. Due to their low antioxidant capacity, insulin producing pancreatic β-cells are sensitive to increased lipid oxidation and related generation of reactive oxygen species. Thus, PCSK9 inhibition has been argued to promote diabetes like statins. Potentially, the remaining patients at risk will be identified in the future. Otherwise, there is increasing evidence that loss of circulating PCSK9 does not worsen glycaemia since it is compensated by local PCSK9 expression in β-cells and other islet cells. This review explores the situation in β-cells. We evaluated the relevant biology of PCSK9 and the effects of its functional loss in rodent knockout models, carriers of LDL-lowering gene variants and PCSK9 inhibitor-treated patients.

show abstract

Section: Expression In Extrahepatic Tissuesmentioning

confidence: 90%

PCSK9 inhibition and cholesterol homeostasis in insulin producing β-cells

et al. 2022

View full text Add to dashboard Cite

show abstract

“…While there is consensus on the identification of PCSK9 in the Langerhans' islets [34], uncertainty remains relative to the exact location, some studies reporting protein expression of PCSK9 in δ-cells, with no detectable expression in α-and β-cells of Pcsk9 −/− mice [35], and others indicating that murine β-cells do express PCSK9 [34,36]. In line with this latter, not only the expression of PCSK9 was found in human pancreatic β-cells [37,38], but these cells were reported to secrete PCSK9.…”

Section: Preclinical Studiesmentioning

confidence: 94%

“…Looking at the physiological role played by PCSK9, in fully Pcsk9 −/− mice, the expression of LDLR was raised in β cells [ 39 ], although it is important to note that PCSK9 regulates multiple cell surface receptors in pancreatic β-cells, namely, very low-density lipoprotein receptor levels, as well as levels of cluster of differentiation 36 (CD36), a fatty acid transporter [ 38 ].…”

Section: Which Role Does Pcsk9 Play In β-Cells?mentioning

confidence: 99%

PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

Carugo

Sirtori

Corsini

et al. 2022

Curr Atheroscler Rep

View full text Add to dashboard Cite

Purpose of Review Since the clinical benefit of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors occurs in a setting of reducing low-density lipoprotein-cholesterol (LDL-C) to unprecedentedly low levels, it becomes of interest to investigate possible adverse effects pertaining to the risk of new-onset diabetes (NOD). Recent Findings While safety results reported in either meta-analyses or cardiovascular outcome trials FOURIER (with evolocumab) and ODYSSEY (with alirocumab) did not rise the incidence of NOD, Mendelian randomization analyses were almost concordant in showing an increased risk of NOD. This evidence was in line with post-marketing safety reports highlighting that evolocumab and alirocumab were primarily related to mild hyperglycaemia rather than diabetes, with most of the hyperglycaemic events occurring during the first 6 months of treatment. Summary Considering the different nature of genetic studies and of randomized controlled trials, with careful monitoring of patients, particularly in the earlier phases of treatment, and the identification of those more susceptible to develop NOD, treatment with PCSK9 inhibitors should be of minimal concern.

show abstract

“…PCSK9 level is positively associated with fasting plasma glucose, glycosylated haemoglobin, total cholesterol, and LDL-C levels in patients with GDM ( 140 ). PCSK9 deficiency leads to an increased expression of LDLR in pancreatic β-cells ( 141 ). PCSK9 knockdown also promotes intracellular cholesterol accumulation, islet function and insulin secretion ( 141 , 142 ).…”

Section: Roles Of Pcsk9 In Thrombosis and Haemostasis Under Disease S...mentioning

confidence: 99%

“…PCSK9 deficiency leads to an increased expression of LDLR in pancreatic β-cells ( 141 ). PCSK9 knockdown also promotes intracellular cholesterol accumulation, islet function and insulin secretion ( 141 , 142 ). Specifically, PCSK9 interacts with human pancreatic β-cells through LDLR and an intracellular signalling mechanism that regulates the expression of CD36, anti-programmed death 1 and HLA-ABC receptors ( 141 ).…”

Section: Roles Of Pcsk9 In Thrombosis and Haemostasis Under Disease S...mentioning

confidence: 99%

Effects of PCSK9 on thrombosis and haemostasis in a variety of metabolic states: Lipids and beyond (Review)

Chong,

Mu,

Cen

et al. 2024

Int J Mol Med

View full text Add to dashboard Cite

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are widely recognised as being able to induce a potent reduction in low-density lipoprotein-cholesterol. An increasing number of studies have suggested that PCSK9 also influences the haemostatic system by altering platelet function and the coagulation cascade. These findings have significant implications for anti-PCSK9 therapy in patients with specific coagulation conditions, including expanded indications, dose adjustments and drug interactions. The present review summarises the changes in PCSK9 levels in individuals with liver diseases, chronic kidney diseases, diabetes mellitus, cancer and other disease states, and discusses their impact on thrombosis and haemostasis. Furthermore, the structure, effects and regulatory mechanisms of PCSK9 on platelets, coagulation factors, inflammatory cells and endothelial cells during coagulation and haemostasis are described.

show abstract

Proprotein convertase PCSK9 affects expression of key surface proteins in human pancreatic beta cells via intracellular and extracellular regulatory circuits

Cited by 7 publications

References 60 publications

PCSK9 inhibition and cholesterol homeostasis in insulin producing β-cells

PCSK9 inhibition and cholesterol homeostasis in insulin producing β-cells

PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

Effects of PCSK9 on thrombosis and haemostasis in a variety of metabolic states: Lipids and beyond (Review)

Contact Info

Product

Resources

About