Proteolysis of Apolipoprotein A-I by Secretory Phospholipase A2

Cavigiolio, Giorgio; Jayaraman, Sundararajan

doi:10.1074/jbc.m113.525717

Cited by 29 publications

(17 citation statements)

References 65 publications

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“…Oxidized TG-HDL obtained by these methods were remodeled by incubation with 3 M Gdn HCl as described above, and the products of this remodeling were isolated either by SEC or by density centrifugation for further studies. Oxidation-induced change in the molecular weight of free apoA-I separated by this method was determined by MALDI-TOF as previously described [56]. …”

Section: Methodsmentioning

confidence: 99%

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Triglyceride increase in the core of high-density lipoproteins augments apolipoprotein dissociation from the surface: Potential implications for treatment of apolipoprotein deposition diseases

Jayaraman

Sánchez-Quesada²,

Gursky

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Lipids in the body are transported via lipoproteins that are nanoparticles comprised of lipids and amphipathic proteins termed apolipoproteins. This family of lipid surface-binding proteins is over-represented in human amyloid diseases. In particular, all major proteins of high-density lipoproteins (HDL), including apoA-I, apoA-II and serum amyloid A, can cause systemic amyloidoses in humans upon protein mutations, post-translational modifications or overproduction. Here, we begin to explore how the HDL lipid composition influences amyloid deposition by apoA-I and related proteins. First, we summarize the evidence that, in contrast to lipoproteins that are stabilized by kinetic barriers, free apolipoproteins are labile to misfolding and proteolysis. Next, we report original biochemical and biophysical studies showing that increase in triglyceride content in the core of plasma or reconstituted HDL destabilizes the lipoprotein assembly, making it more labile to various perturbations (oxidation, thermal and chemical denaturation and enzymatic hydrolysis), and promotes apoA-I release in a lipid-poor/free aggregation-prone form. Together, the results suggest that decreasing plasma levels of triglycerides will shift the dynamic equilibrium from the lipid-poor/free (labile) to the HDL-bound (protected) apolipoprotein state, thereby decreasing the generation of the protein precursor of amyloid. This prompts us to propose that triglyceride-lowering therapies may provide a promising strategy to alleviate amyloid diseases caused by the deposition of HDL proteins.

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Section: Methodsmentioning

confidence: 99%

“…Known amounts of dry lipids were analyzed using either hexane : ether : acetic acid (70:30:1 molar ratio) or chloroform : methanol : water : acetic acid (65:25:4:1 molar ratio) to separate apolar or polar lipids, respectively, as previously described [56]. …”

Section: Methodsmentioning

confidence: 99%

Triglyceride increase in the core of high-density lipoproteins augments apolipoprotein dissociation from the surface: Potential implications for treatment of apolipoprotein deposition diseases

Jayaraman

Sánchez-Quesada²,

Gursky

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…ApoE-deficient (ApoE –/–) mice display enhanced chronic inflammatory responses to diet-induced hypercholesterolemia [10, 11]. Therefore, 12-weeks of high fat diet (HFD) on (ApoE –/–) mice have been used to develop AS model for years [13-15]. …”

Section: Introductionmentioning

confidence: 99%

Upregulation of microRNA-876 Induces Endothelial Cell Apoptosis by Suppressing Bcl-Xl in Development of Atherosclerosis

Liu

Zhao

2017

Cell Physiol Biochem

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Background/Aims: The injury and apoptotic cell death of endothelial cells hallmark the development of atherosclerosis (AS), characterized by dysregulation of lipid homeostasis, immune responses, and formation of coronary plaques. However, the mechanisms underlying the initiation of endothelial cell apoptosis remain ill-defined. Recent evidence suggests a role of microRNAs in the processes of AS-associated endothelial cell apoptosis. Thus, we studied this question in the current study. Methods: AS was developed in ApoE (-/-) mice suppled with high-fat diet (HFD), compared to ApoE (-/-) mice suppled with normal diet (ND). Mouse endothelial cells were isolated from the aortic arch using flow cytometry based on their expression of Pecam-1. Oxidized low-density lipoprotein (ox-LDL) were used to treat human aortic endothelial cells (HAECs) as an in vitro model for AS. Gene expression was quantified by RT-qPCR and protein levels were analyzed by Western blotting. Apoptosis was evaluated by FITC Annexin V Apoptosis essay and by TUNEL staining. Prediction of the binding between miRNAs and 3'-UTR of mRNA from the target gene was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. Results: HFD mice, but not ND mice, developed AS in 12 weeks. Significantly reduced endothelial cell marks and significantly increased mesenchymal cell marks were detected in the aortic arch of the HFD mice, compared to the ND mice. The endothelial cell apoptosis was significantly higher in HFD mice, seemingly due to functional suppression of protein translation of anti-apoptotic Bcl-Xl protein through upregulation of miR-876. Similar results were obtained from in vitro study. Inhibition of miR-876 abolished the effects of ox-LDL-induced apoptotic cell death of HAECs. Conclusion: AS-associated endothelial cell apoptosis may partially result from downregulation of Bcl-Xl, through upregulation of miR-876 that binds and suppresses translation of Bcl-Xl mRNA.

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“…A novel report by Cavigiolio and Jayaraman [85] indicated that certain sPLA 2 s are capable of acting as proteolytic enzymes. They demonstrated the effect by hydrolyzing the apolipoprotein A1 (apoA1) on HDL.…”

Section: Unexpected Proteolytic Properties Of Splamentioning

confidence: 99%

Diverse Functions of Secretory Phospholipases A₂

Shridas

Webb

2014

Advances in Vascular Medicine

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Phospholipase A 2 enzymes (PLA 2 s) catalyze the hydrolysis of glycerophospholipids at their sn-2 position releasing free fatty acids and lysophospholipids. Mammalian PLA 2 s are classified into several categories of which important groups include secreted PLA 2 s (sPLA 2 s) and cytosolic PLA 2 s (cPLA 2 s) that are calcium-dependent for their catalytic activity and calcium-independent cytosolic PLA 2 s (iPLA 2 s). Platelet-activating factor acetylhydrolases (PAF-AHs), lysosomal PLA 2 s, and adipose-specific PLA 2 also belong to the class of PLA 2 s. Generally, cPLA 2 enzymes are believed to play a major role in the metabolism of arachidonic acid, the iPLA 2 family to membrane homeostasis and energy metabolism, and the sPLA 2 family to various biological processes. The focus of this review is on recent research developments in the sPLA 2 field. sPLA 2 s are secreted enzymes with low molecular weight (with the exception of GIII sPLA 2 ), Ca 2+ -requiring enzymes with a His-Asp catalytic dyad. Ten enzymatically active sPLA 2 s and one devoid of enzymatic activity have been identified in mammals. Some of these sPLA 2 s are potent in arachidonic acid release from cellular phospholipids for the biosynthesis of eicosanoids, especially during inflammation. Individual sPLA 2 enzymes exhibit unique tissue and cellular localizations and specific enzymatic properties, suggesting their distinct biological roles. Recent studies indicate that sPLA 2 s are involved in diverse pathophysiological functions and for most part act nonredundantly.

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Proteolysis of Apolipoprotein A-I by Secretory Phospholipase A2

Cited by 29 publications

References 65 publications

Triglyceride increase in the core of high-density lipoproteins augments apolipoprotein dissociation from the surface: Potential implications for treatment of apolipoprotein deposition diseases

Triglyceride increase in the core of high-density lipoproteins augments apolipoprotein dissociation from the surface: Potential implications for treatment of apolipoprotein deposition diseases

Upregulation of microRNA-876 Induces Endothelial Cell Apoptosis by Suppressing Bcl-Xl in Development of Atherosclerosis

Diverse Functions of Secretory Phospholipases A₂

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Proteolysis of Apolipoprotein A-I by Secretory Phospholipase A2

Cited by 29 publications

References 65 publications

Triglyceride increase in the core of high-density lipoproteins augments apolipoprotein dissociation from the surface: Potential implications for treatment of apolipoprotein deposition diseases

Triglyceride increase in the core of high-density lipoproteins augments apolipoprotein dissociation from the surface: Potential implications for treatment of apolipoprotein deposition diseases

Upregulation of microRNA-876 Induces Endothelial Cell Apoptosis by Suppressing Bcl-Xl in Development of Atherosclerosis

Diverse Functions of Secretory Phospholipases A2

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Diverse Functions of Secretory Phospholipases A₂