The life cycle of the low-density lipoprotein receptor

Wijers, Melinde; Kuivenhoven, Jan Albert; Sluis, Bart van de

doi:10.1097/mol.0000000000000157

Cited by 49 publications

(33 citation statements)

References 61 publications

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“…This would lead to downregulation of both PCSK9 and LDLR by SREBP2 [9,10]. However, in the present study, conjugated bilirubin showed a weaker correlation with PCSK9 compared to the unconjugated bilirubin.…”

Section: Discussioncontrasting

confidence: 53%

“…However, sterol regulatory element binding protein 2 (SREBP2) seems to play an important role, as it promotes the expression of PCSK9. The activation of SREBPs is linked to intracellular sterol levels, with activation occurring in response to decreases in these levels [9]. Interestingly, SREBP2 promotes the expression of both LDL receptor (LDLR) and PCSK9, which plays a key role in the regulation of the LDLR [10].…”

Section: Introductionmentioning

confidence: 99%

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Low PCSK9 levels are correlated with mortality in patients with end-stage liver disease

et al. 2017

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IntroductionProprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in the cholesterol metabolism and is synthesized by the liver. It interacts with the LDL-receptor to promote its degradation. The model of end-stage liver disease (MELD) score is a well-established tool to estimate the risk of mortality in patients with end-stage chronic liver disease. The study aims to assess the associations between PCSK9, hypocholesterinemia, liver synthesis, cholestasis, MELD score and mortality in patients with end-stage liver disease.MethodsSerum samples were obtained from 74 patients with severe liver disease. The study participants were aged between 23 and 70 y (mean: 55.8 y; 47 males [63.5%], 27 females [36.5%]). Samples were selected from those with a wide range of MELD scores (7 to 40).Patients that underwent liver transplantation (17 / 74) were censored at the time of transplantation for mortality analysis.ResultsPCSK9 values ranged from 31.47 ng/mL to 261.64 ng/mL. The median value was 106.39 ng/ml. PCSK9 was negatively correlated with markers of liver function and cholestasis (INR, bilirubin). Over a 90-d follow-up, 15 of 57 (26,3%) patients died within the 90-d follow-up without receiving liver transplantation. Thirteen of 31 (42%) patients with PCSK9 levels below the median died compared to 2/26 (8%) patients with higher PCSK9 levels (p = 0.006). In this cohort, there were no significant correlations between PCSK9, cholesterol, its precursors and several phytosterols.ConclusionsLow PCSK9 serum concentrations were associated with higher mortality in patients with end-stage liver disease. The mean PCSK9 levels in the study population were much lower than those found in normal or healthy populations. Further studies are required to acquire a more detailed understanding of the role of PCSK9 in liver-related mortality.

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Section: Discussioncontrasting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Low PCSK9 levels are correlated with mortality in patients with end-stage liver disease

et al. 2017

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“…LDL and LDLR are endocytosed together (Fig. 1), which is mediated by several adaptor proteins such as autosomal recessive hypercholesterolemia (ARH) protein, and Disabled homolog 2 (DAB2) protein (reviewed in [11*]) (Fig. 1A).…”

Section: Low-density Lipoprotein Receptor (Ldlr)mentioning

confidence: 99%

“…1). Although the transport of IDOL-mediated LDLR degradation is ARH-independent, it requires the endosomal-sorting complex required for transport machinery (ESCRT) to direct LDLR towards the lysosomes (reviewed in [11*,17*]). Intriguingly, however, for reasons that are not understood, IDOL has no significant effect on the degradation of LDLR in murine livers, but might have a potential role in LDLR proteolysis in human and monkey livers [18*].…”

Section: Low-density Lipoprotein Receptor (Ldlr)mentioning

confidence: 99%

News on the molecular regulation and function of hepatic low-density lipoprotein receptor and LDLR-related protein 1

Sluis

Wijers

Herz

2017

Current Opinion in Lipidology

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Purpose of review Clearing of atherogenic lipoprotein particles by the liver requires hepatic LDLR and LRP1. This review highlights recent studies that have expanded out understanding of the molecular regulation and metabolic functions of LDLR and LRP1 in the liver. Recent findings Various proteins orchestrate the intracellular trafficking of LDLR and LRP1. After internalization, the receptors are redirected via recycling endosomes to the cell surface. Several new endocytic proteins that facilitate the endosomal trafficking of LDLR and consequently the clearance of circulating LDL cholesterol have recently been reported. Mutations in some of these proteins cause hypercholesterolemia in human. In addition, LRP1 controls cellular cholesterol efflux by modulating the expression of ABCA1, and ABCG1, and hepatic LRP1 protects against diet-induced hepatic insulin resistance and steatosis through the regulation of insulin receptor trafficking. Summary LDLR and LRP1 have prominent roles in cellular and organismal cholesterol homeostasis. Their functioning, including their trafficking in the cell, is controlled by numerous proteins. Comprehensive studies into the molecular regulation of LDLR and LRP1 trafficking have advanced our fundamental understanding of cholesterol homeostasis, and these insights may lead to novel therapeutic strategies for atherosclerosis, hyperlipidemia and insulin resistance in the future.

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“…The cargo transported via this pathway is manifold such as LDL receptors [34], MHC receptors [35], CD3 receptors [36, 37] or transferrin receptors [38]. In addition, solutes, SNARE and SNARE-associated proteins and G-protein coupled receptors are also recycled via RE.…”

Section: Endosomal Networkmentioning

confidence: 99%

Preparing the lethal hit: interplay between exo- and endocytic pathways in cytotoxic T lymphocytes

Chang

Bzeih

Chitirala

et al. 2016

Cell. Mol. Life Sci.

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Cytotoxic T lymphocytes patrol our body in search for infected cells which they kill through the release of cytotoxic substances contained in cytotoxic granules. The fusion of cytotoxic granules occurs at a specially formed contact site, the immunological synapse, and is tightly controlled to ensure specificity. In this review, we discuss the contribution of two intracellular compartments, endosomes and cytotoxic granules, to the formation, function and disassembly of the immunological synapse. We highlight a recently proposed sequential process of fusion events at the IS upon target cell recognition. First, recycling endosomes fuse with the plasma membrane to deliver cargo required for the docking of cytotoxic granules. Second, cytotoxic granules arrive and fuse upon docking in a SNARE-dependent manner. Following fusion, membrane components of the cytotoxic granule are retrieved through endocytosis to ensure the fast, efficient serial killing of target cells that is characteristic of cytotoxic T lymphocytes.

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The life cycle of the low-density lipoprotein receptor

Cited by 49 publications

References 61 publications

Low PCSK9 levels are correlated with mortality in patients with end-stage liver disease

Low PCSK9 levels are correlated with mortality in patients with end-stage liver disease

News on the molecular regulation and function of hepatic low-density lipoprotein receptor and LDLR-related protein 1

Preparing the lethal hit: interplay between exo- and endocytic pathways in cytotoxic T lymphocytes

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