Low density lipoprotein misfolding and amyloidogenesis

Parasassi, Tiziana; Spirito, Marco De; Mei, Giampiero; Brunelli, Roberto; Greco, Giulia; Lenzi, Laura; Maulucci, Giuseppe; Nicolai, Eleonora; Papi, Massimiliano; Arcòvito, Giuseppe; Tosatto, Silvio C. E.; Ursini, Fulvio

doi:10.1096/fj.07-097774

Cited by 50 publications

(48 citation statements)

References 37 publications

(46 reference statements)

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“…This process was paralleled by phospholipid degradation. These results concur with previous studies reporting that in the absence of physical or chemical stimuli, total LDL(Ϫ) aggregates to form amyloid-like fibrils in a period of one to several days and that it can promote the spontaneous aggregation of native LDL (18). Our results suggest that amyloidogenesis promoted by LDL(Ϫ) could be specifically due to agLDL(Ϫ) in a process involving PLC-like activity.…”

Section: Discussionsupporting

confidence: 93%

“…Studies performed in endothelial and mononuclear cells have shown that LDL(Ϫ) induces inflammation and apoptosis and impairs angiogenesis (11)(12)(13)(14). Regarding its physicochemical characteristics, apolipoprotein B-100 (apoB) in LDL(Ϫ) presents structural differences versus apoB in native LDL (15), binds poorly to the LDL receptor (16), is prone to aggregation (17), and presents amyloidogenic properties (18). Our group recently reported that LDL(Ϫ) has several populations with normal or high binding affinity to proteoglycans compared with native LDL (1).…”

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confidence: 99%

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Aggregated Electronegative Low Density Lipoprotein in Human Plasma Shows a High Tendency toward Phospholipolysis and Particle Fusion

Bancells

Villegas

Blanco

et al. 2010

Journal of Biological Chemistry

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Aggregation and fusion of lipoproteins trigger subendothelial retention of cholesterol, promoting atherosclerosis. The tendency of a lipoprotein to form fused particles is considered to be related to its atherogenic potential. We aimed to isolate and characterize aggregated and nonaggregated subfractions of LDL from human plasma, paying special attention to particle fusion mechanisms. Aggregated LDL was almost exclusively found in electronegative LDL (LDL(؊)), a minor modified LDL subfraction, but not in native LDL (LDL(؉)). The main difference between aggregated (agLDL(؊)) and nonaggregated LDL(؊) (nagLDL(؊)) was a 6-fold increased phospholipase C-like activity in agLDL(؊). agLDL(؊) promoted the aggregation of LDL(؉) and nagLDL(؊). Lipoprotein fusion induced by ␣-chymotrypsin proteolysis was monitored by NMR and visualized by transmission electron microscopy. Particle fusion kinetics was much faster in agLDL(؊) than in nagLDL(؊) or LDL(؉). NMRand chromatographic analysis revealed a rapid and massive phospholipid degradation in agLDL(؊) but not in nagLDL(؊) or LDL(؉). Choline-containing phospholipids were extensively degraded, and ceramide, diacylglycerol, monoacylglycerol, and phosphorylcholine were the main products generated, suggesting the involvement of phospholipase C-like activity. The properties of agLDL(؊) suggest that this subfraction plays a major role in atherogenesis by triggering lipoprotein fusion and cholesterol accumulation in the arterial wall.

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Section: Discussionsupporting

confidence: 93%

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confidence: 99%

Aggregated Electronegative Low Density Lipoprotein in Human Plasma Shows a High Tendency toward Phospholipolysis and Particle Fusion

Bancells

Villegas

Blanco

et al. 2010

Journal of Biological Chemistry

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“…The binding of apoJ to unfolded proteins promotes its recognition by LDL-receptor-related protein 2 (LRP2) and favors its clearance and degradation ( 30 ). Interestingly, LDL( Ϫ ) presents some structural abnormalities, including particle aggregation ( 32 ) and apoB misfolding ( 33,34 ), that could be related to the presence of apoJ in this subfraction.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of electronegative low-density lipoprotein

Bancells

Canals

Benı́tez

et al. 2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org LDL, the main cholesterol carrier in plasma, is composed of approximately 75% lipid (mainly cholesterol) and 25% protein. The major protein in LDL is apolipoprotein B-100 (apoB-100), a protein of 550 kDa that accounts for more than 95% of the total protein mass in LDL ( 1 ). However, minor amounts of other apolipoproteins associated to LDL have been reported. Several of these proteins, such as apoE, apoC-III, and platelet-activating factor acetylhydrolase (PAF-AH), have important roles in LDL metabolism and modulate its atherogenicity despite their low concentration ( 2-4 ). Several studies have made a proteomic approach using 2D-electrophoresis or SELDI-based analysis to detect minor proteins in LDL ( 5-9 ), including apoE, apoC-III, apoC-II, apoA-I, apoA-IV, apoM, apoJ, serum amyloid A4 (SAA4), calgranulin A, lysozyme C, apoD, apoH, ␣ 1-antitrypsin, orosomucoid-1, paraoxonase-1, retinol binding protein, and prenylcysteine lyase-1.LDL is not a homogeneous entity but a group of particles that differs in density, size, electric charge, and composition. It is well established that small, dense LDL particles are more atherogenic than large, buoyant particles ( 10 ), and both of these subfractions differ in their protein content ( 6 ). Another property of LDL that confers enhanced atherogenicity is increased electronegative charge. Electronegative LDL [LDL( Ϫ )] is a minor subfraction of plasma LDL that is pro-infl ammatory and induces apoptosis in endothelial cells and leukocytes ( 11-13 ). Its relative proportion is increased in subjects Abstract Low density lipoprotein is a heterogeneous group of lipoproteins that differs in lipid and protein composition. One copy of apolipoprotein (apo)B accounts for over 95% of the LDL protein, but the presence of minor proteins could disturb its biological behavior. Our aim was to study the content of minor proteins in LDL subfractions separated by anion exchange chromatography. 29 July 2010. Published, JLR Papers in Press, August 10, 2010 DOI 10.1194 Abbreviations: apo, apolipoprotein; BHT, butylated hydroxytoluene; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; GGE, non-denaturing gradient gel electrophoresis; LDL(+), electropositive low-density lipoprotein; LDL( Ϫ ), electronegative low-density lipoprotein; Lp(a), lipoprotein (a); LRP2, low-density lipoprotein receptor-related protein 2; PAF-AH, platelet-activating factor-acetylhydrolase; SAA4, serum amyloid A4; TG, triglyceride; TTBS, Tweencontaining tris buffer saline. Supplementary key words apolipoproteins • atherosclerosis • modifi ed LDL This work was supported by Ministerio de Sanidad/Instituto de Salud Carlos III/FIS (ISCIII/FIS) Grants PI060500, CP040110 (S.B.), and CP060220 (JLS-Q.); and Ministerio de Educación y Ciencia Grant AP2004-1468 (C.B). The Proteomics Laboratory at Vall d'Hebron Research Institute is a member of the Instituto Nacional de Proteómica (ProteoRed) funded by Fundación Genoma España. CIBER de Diabetes y Enfermedades M...

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“…303) During aggregation, a dominostyle spread of apoB-100 misfolding from LDL(−) to all of the LDL particles occurs. 303) It has been predicted that a structure in the α 2 domain is highly prone to a conformational switch from a native α-helical arrangement toward cross-β aggregation with other protein molecules.…”

Section: Apob Denaturationmentioning

confidence: 99%

“…307) However, the overall secondary structure of lipid-free apoB is highly conserved, suggesting the solubilization of lipid-free apoB by NaDC may lead to only partial unfolding of the secondary structure in apoB rather than global protein unfolding as shown in oxLDL or LDL(−). 299,300,303,307,308) I have investigated the cytotoxic effect of lipid-free apoB solubilized with NaDC, as a model for denatured apoB. Lipidfree apoB has cytotoxicity to J774 macrophages, HepG2 cells and Chinese hamster ovary cells, whereas LDL-apoB and lipid-free apoA-I have no effect on the cell viability.…”

Section: Apob Denaturationmentioning

confidence: 99%

Metabolism and Modification of Apolipoprotein B-Containing Lipoproteins Involved in Dyslipidemia and Atherosclerosis

Morita

2016

Biological & Pharmaceutical Bulletin

133

108

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Increased levels of apolipoprotein B (apoB)-containing lipoproteins, such as low density lipoproteins (LDL) and chylomicron remnants, are associated with the development of atherosclerosis. Chylomicrons containing apoB-48 are secreted from the intestine during the postprandial state, whereas very low density lipoproteins (VLDL) containing apoB-100 are constitutively formed in the liver. Chylomicron remnants and VLDL remnants are produced by the lipoprotein lipase-mediated lipolysis of triglycerides, which is activated by apolipoprotein C-II bound on the particle surfaces. The hepatic uptake of these remnants is facilitated by apolipoprotein E (apoE), but is inhibited by apolipoproteins C-I, C-II and C-III. In the plasma, VLDL remnants are further converted into LDL by the hydrolysis of triglycerides. ApoB-100 is responsible for the hepatic uptake of LDL. LDL receptor, LDL receptor-related protein and heparan sulfate proteoglycans are involved in the hepatic clearance of lipoproteins containing apoB-100 and/or apoE. The subendothelial retention and modification of apoB-containing lipoproteins are crucial events in the initiation of atherosclerosis. In the subendothelium, the uptake of modified lipoproteins by macrophages leads to the formation of foam cells storing excess amounts of cholesteryl esters and subsequently to apoptosis. This review describes the current knowledge about the metabolism and modification of apoB-containing lipoproteins involved in dyslipidemia and atherogenesis. In particular, I focus on the effects of apolipoproteins, lipid composition and particle size on lipoprotein metabolism and on the roles of cholesterol, sphingomyelinase and apoB denaturation in macrophage foam cell formation and apoptosis. A detailed understanding of these mechanisms will help to develop new therapeutic strategies.

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Low density lipoprotein misfolding and amyloidogenesis

Cited by 50 publications

References 37 publications

Aggregated Electronegative Low Density Lipoprotein in Human Plasma Shows a High Tendency toward Phospholipolysis and Particle Fusion

Aggregated Electronegative Low Density Lipoprotein in Human Plasma Shows a High Tendency toward Phospholipolysis and Particle Fusion

Proteomic analysis of electronegative low-density lipoprotein

Metabolism and Modification of Apolipoprotein B-Containing Lipoproteins Involved in Dyslipidemia and Atherosclerosis

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