Lipoprotein(a) Cellular Uptake Ex Vivo and Hepatic Capture In Vivo Is Insensitive to PCSK9 Inhibition With Alirocumab

Chemello, BS Kévin; Beeské, Sandra; Tran, Thi Thu Trang; Blanchard, BS Valentin; Villard, Elise F.; Poirier, Bruno; Bail, Jean-Christophe Le; Dargazanli, Gihad; Ho-Van-Guimbal, Sophie; Boulay, Denis; Bergis, Olivier; Pruniaux, Marie-Pierre; Croyal, Mikaël; Janiak, Philip; Guillot, Etienne; Lambert, Gilles

doi:10.1016/j.jacbts.2020.03.008

Cited by 23 publications

(15 citation statements)

References 23 publications

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“…We recently reported that the cellular uptake of Lp(a) was similar in primary lymphocytes isolated from patients with HoFH and healthy donors ( 65 ). In vivo, the pharmacological modulation of the LDLR using PCSK9 inhibitors did significantly affect neither the fractional catabolic rate (FCR) of Lp(a) in nonhuman primates ( 66 ) nor the hepatic capture of fluorescently labeled Lp(a) in liver humanized mice ( 65 ). In humans, the FCR of Lp(a) was not statistically different between control individuals and HeFH or HoFH patients separately, but compared with non-FH controls, the FCR of Lp(a) was significantly reduced when combining all patients with FH ( 60 , 67 ).…”

Section: Lipoprotein Metabolism In Fh Beyond Ldlmentioning

confidence: 95%

“…For instance, in vitro, the binding and cellular uptake of Lp(a) is reduced in primary HoFH dermal fibroblasts totally lacking the LDLR in some studies but not in others (63,64). We recently reported that the cellular uptake of Lp(a) was similar in primary lymphocytes isolated from patients with HoFH and healthy donors (65). In vivo, the pharmacological modulation of the LDLR using PCSK9 inhibitors did significantly affect neither the fractional catabolic rate (FCR) of Lp(a) in nonhuman primates (66) nor the hepatic capture of fluorescently labeled Lp(a) in liver humanized mice (65).…”

Section: Lipoprotein (A)mentioning

confidence: 98%

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Lipoprotein metabolism in familial hypercholesterolemia

Chemello

García-Nafría

Gallo

et al. 2021

Journal of Lipid Research

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Familial hypercholesterolemia (FH) is one of the most common genetic disorders in humans. It is an extremely atherogenic metabolic disorder characterized by lifelong elevations of circulating LDL-C levels often leading to premature cardiovascular events. In this review, we discuss the clinical phenotypes of heterozygous and homozygous FH, the genetic variants in four genes ( LDLR/APOB/PCSK9/LDLRAP1 ) underpinning the FH phenotype as well as the most recent in vitro experimental approaches used to investigate molecular defects affecting the LDL receptor pathway. In addition, we review perturbations in the metabolism of lipoproteins other than LDL in FH, with a major focus on lipoprotein (a). Finally, we discuss the mode of action and efficacy of many of the currently approved hypocholesterolemic agents used to treat patients with FH, with a special emphasis on the treatment of phenotypically more severe forms of FH.

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Section: Lipoprotein Metabolism In Fh Beyond Ldlmentioning

confidence: 95%

Section: Lipoprotein (A)mentioning

confidence: 98%

Lipoprotein metabolism in familial hypercholesterolemia

Chemello

García-Nafría

Gallo

et al. 2021

Journal of Lipid Research

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“…Numerous animal studies help to interpret clinching data on the metabolism of the role of Lp(a) and its metabolic characteristics [ 36 , 37 ]. It was shown that modulation of LDLR expression with the PCSK9 inhibitor alirocumab did not alter the cellular or the hepatic uptake of Lp(a), LDL receptor is not a major route for Lp(a) plasma clearance [ 37 ]. This research has some limitations.…”

Section: Proprotein Convertase Subtilisin/kexin Type 9 Inhibitors (Pcsk9i)mentioning

confidence: 99%

Modern Approaches to Lower Lipoprotein(a) Concentrations and Consequences for Cardiovascular Diseases

2021

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Lipoprotein(a) (Lp(a)) is a low density lipoprotein particle that is associated with poor cardiovascular prognosis due to pro-atherogenic, pro-thrombotic, pro-inflammatory and pro-oxidative properties. Traditional lipid-lowering therapy does not provide a sufficient Lp(a) reduction. For PCSK9 inhibitors a small reduction of Lp(a) levels could be shown, which was associated with a reduction in cardiovascular events, independently of the effect on LDL cholesterol. Another option is inclisiran, for which no outcome data are available yet. Lipoprotein apheresis acutely and in the long run decreases Lp(a) levels and effectively improves cardiovascular prognosis in high-risk patients who cannot be satisfactorily treated with drugs. New drugs inhibiting the synthesis of apolipoprotein(a) (an antisense oligonucleotide (Pelacarsen) and two siRNA drugs) are studied. Unlike LDL-cholesterol, for Lp(a) no target value has been defined up to now. This overview presents data of modern capabilities of cardiovascular risk reduction by lowering Lp(a) level.

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“…Multiple receptors have been implicated in binding Lp(a) and mediating Lp(a) endocytic uptake into the cell including the LDL receptor (Floren et al, 1981; Hofmann et al, 1990; Romagnuolo et al, 2017; Tam et al, 1996), VLDL receptor (Argraves et al, 1997) and plasminogen receptors (Sharma et al, 2017), yet in each case the impact of each receptor on Lp(a) uptake is either inconsistent or only partially responsible for uptake, leaving our understanding of the process of Lp(a) catabolism incomplete (Chemello et al, 2020; McCormick and Schneider, 2019; Rader et al, 1995; Reblin et al, 1997; Romagnuolo et al, 2017). Genome-wide association studies have revealed associations between Lp(a) levels and single nucleotide polymorphisms in genes coding for regulators of endocytic processes such as SNX9 and apoE (Lu et al, 2015; Mack et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Multiple receptors have been implicated in binding Lp(a) and mediating Lp(a) endocytic uptake into the cell including the LDL receptor 8–11 , VLDL receptor 12 and plasminogen receptors 13 , yet in each case the impact of each receptor on Lp(a) uptake is either inconsistent or only partially responsible for uptake, leaving our understanding of the process of Lp(a) catabolism incomplete 11,14–17 . Given the multitude of receptors implicated in Lp(a) uptake without any clearly defined mechanistic role in Lp(a) endocytosis, we hypothesised that Lp(a) uptake occurs via the endocytic process called macropinocytosis.…”

Section: Introductionmentioning

confidence: 99%

Antidepressants stimulate lipoprotein(a) macropinocytosis via serotonin-enhanced cell surface binding

Redpath

Deo

Siddiqui

et al. 2021

Preprint

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The regulation of Lp(a) clearance from circulation by cellular uptake remains enigmatic. While multiple receptors have been implicated in Lp(a) uptake, each receptor only partially accounts for this uptake, and no endocytic mechanism has yet been prescribed for Lp(a) internalisation into the cell. In this study, we define macropinocytosis as the endocytic pathway responsible for internalising Lp(a). In both liver and macrophage cells, Lp(a) uptake is dependent on extracellular calcium and is inhibited by amiloride or its derivative EIPA. The uptake of apo(a) alone is mediated by macropinocytosis, indicating the apo(a) protein component is a primary regulator of Lp(a) uptake. Importantly, we found that common antidepressants modulate Lp(a) macropinocytosis in cell-type dependent manners. In macrophages, the tricyclic antidepressant, imipramine and selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine and sertraline all inhibit Lp(a) uptake. In liver cells, imipramine and citalopram strongly stimulated Lp(a) uptake, while sertraline inhibited uptake. Imipramine and citalopram enhanced Lp(a) uptake by enhancing cell surface binding of Lp(a) rather than upregulating macropinocytosis per se, indicating that immobilisation of Lp(a) on the plasma membrane is an important regulatory step in Lp(a) macropinocytosis. As the liver is the major catabolic route for Lp(a), we dissected the functional consequences of imipramine and citalopram stimulated uptake in liver cells. Both drugs increased Lp(a) delivery to Rab11-positive recycling endosomes, but not late endosomes or lysosomes, resulting in increased apo(a) recycling into the cellular media. Given that free apo(a) is reported to undergo consistent proteolysis in the extracellular space or in circulation, these results support the potential for the already approved drugs, imipramine and citalopram, as promising therapeutics to lower Lp(a) levels. This approach displays special utility in the large group of people who suffer from depression and anxiety for whom these drugs are commonly prescribed.

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Lipoprotein(a) Cellular Uptake Ex Vivo and Hepatic Capture In Vivo Is Insensitive to PCSK9 Inhibition With Alirocumab

Cited by 23 publications

References 23 publications

Lipoprotein metabolism in familial hypercholesterolemia

Lipoprotein metabolism in familial hypercholesterolemia

Modern Approaches to Lower Lipoprotein(a) Concentrations and Consequences for Cardiovascular Diseases

Antidepressants stimulate lipoprotein(a) macropinocytosis via serotonin-enhanced cell surface binding

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