Fibrillation of human islet amyloid polypeptide and its toxicity to pancreatic β-cells under lipid environment

Gao, Liping; Chen, Haichao; Ma, Zhiqiang; Du, Hong-Li; Yin, Jie; Jing, Yu‐Hong

doi:10.1016/j.bbagen.2019.129422

Cited by 6 publications

(3 citation statements)

References 61 publications

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“…Then, considering that unsaturation and shorter fatty acids of phospholipids facilitate the curvature and fluidity of membranes favoring their fusion [17], although increasing the risk of aggregation, there is a subtle regulation in the conservation of the structure of the hIAPP. Moreover, a report reveals synergic implications of free fatty acids and hIAPP in ER stress and apoptosis of islet β-cells [48]. In this context, we have documented the role of metabolic overload by saturated fatty acids on proteostasis and its impact on insulin secretion, specifically the dysregulation of targets that control intracellular calcium homeostasis [22], as also documented in this report for SERCA2.…”

Section: Discussionsupporting

confidence: 73%

Lipid Modulation in the Formation of β-Sheet Structures. Implications for De Novo Design of Human Islet Amyloid Polypeptide and the Impact on β-Cell Homeostasis

et al. 2020

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Human islet amyloid polypeptide (hIAPP) corresponds to a 37-residue hormone present in insulin granules that maintains a high propensity to form β-sheet structures during co-secretion with insulin. Previously, employing a biomimetic approach, we proposed a panel of optimized IAPP sequences with only one residue substitution that shows the capability to reduce amyloidogenesis. Taking into account that specific membrane lipids have been considered as a key factor in the induction of cytotoxicity, in this study, following the same design strategy, we characterize the effect of a series of lipids upon several polypeptide domains that show the highest aggregation propensity. The characterization of the C-native segment of hIAPP (residues F23-Y37), together with novel variants F23R and I26A allowed us to demonstrate an effect upon the formation of β-sheet structures. Our results suggest that zwitterionic phospholipids promote adsorption of the C-native segments at the lipid-interface and β-sheet formation with the exception of the F23R variant. Moreover, the presence of cholesterol did not modify this behavior, and the β-sheet structural transitions were not registered when the N-terminal domain of hIAPP (K1-S20) was characterized. Considering that insulin granules are enriched in phosphatidylserine (PS), the property of lipid vesicles containing negatively charged lipids was also evaluated. We found that these types of lipids promote β-sheet conformational transitions in both the C-native segment and the new variants. Furthermore, these PS/peptides arrangements are internalized in Langerhans islet β-cells, localized in the endoplasmic reticulum, and trigger critical pathways such as unfolded protein response (UPR), affecting insulin secretion. Since this phenomenon was associated with the presence of cytotoxicity on Langerhans islet β-cells, it can be concluded that the anionic lipid environment and degree of solvation are critical conditions for the stability of segments with the propensity to form β-sheet structures, a situation that will eventually affect the structural characteristics and stability of IAPP within insulin granules, thus modifying the insulin secretion.

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Section: Discussionsupporting

confidence: 73%

Lipid Modulation in the Formation of β-Sheet Structures. Implications for De Novo Design of Human Islet Amyloid Polypeptide and the Impact on β-Cell Homeostasis

et al. 2020

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“…Small hIAPP oligomers with a high surface hydrophobicity formed during the nucleation conformational phase are very toxic, permeate the membrane and produce non-selective pores 19,21,26,28,29,32,40,45–47 . These form highly ordered fibrils with cross-β structure although some aggregates are amorphous assemblies 2,12,16,19,48 , the fibers on the surface of the cell membranes are cytotoxic as well by causing the fragmentation of the membrane by micellization 16,40,45,48 ; recently was demonstrated that tightly mated β-sheet are relevant for toxicity 24,25,49 . Furthermore, the high resolution structure of hIAPP intermediates in the aggregation pathway was attained by nanodisc stabilization 25 .…”

Section: Introductionmentioning

confidence: 99%

Unpacking the aggregation-oligomerization-fibrillization process of naturally-occurring hIAPP amyloid oligomers isolated directly from sera of children with obesity or diabetes mellitus

Altamirano-Bustamante

Larralde-Laborde

et al. 2019

Sci Rep

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The formation of amyloid oligomers and fibrils of the human islet amyloid polypeptide (hIAPP) has been linked with β- cell failure and death which causes the onset, progression, and comorbidities of diabetes. We begin to unpack the aggregation-oligomerization-fibrillization process of these oligomers taken from sera of pediatric patients. The naturally occurring or real hIAPP (not synthetic) amyloid oligomers (RIAO) were successfully isolated, we demonstrated the presence of homo (dodecamers, hexamers, and trimers) and hetero-RIAO, as well as several biophysical characterizations which allow us to learn from the real phenomenon taking place. We found that the aggregation/oligomerization process is active in the sera and showed that it happens very fast. The RIAO can form fibers and react with anti-hIAPP and anti-amyloid oligomers antibodies. Our results opens the epistemic horizon and reveal real differences between the four groups (Controls vs obesity, T1DM or T2DM) accelerating the process of understanding and discovering novel and more efficient prevention, diagnostic, transmission and therapeutic pathways.

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“…The diagnosis of T2DM is often made late, when 60% of the pancreas is destroyed and when β-cell damage is evident; targeting the challenge to identify the metabolically unhealthy children with obesity, using a set of 22 cardiometabolic risk factors such central obesity, waist circumference, relative fat distribution, overall body fatness, signs of insulin resistance, measures of blood pressure, triacylglycerols, HDL-cholesterol, insulin, C-peptide, HOMA, ALT, uric acid, microalbuminuria and plasma glucose among others [5,6]. The damage to the islet is due, in part, to the aggregation state (two or more protein unfolded molecules) of naturallyoccurring cytotoxic oligomers of islet amyloid polypeptide (hIAPP) [7][8][9][10][11][12][13][14][15][16][17] that we called RIAO (Real hIAPP Amyloid Oligomers) [18][19][20]; the aggregation-oligomerization-fibrillization process is active and is well known that there are deposits as amyloid fibrils in more than 90% in patients with T2DM [17,21,22].…”

Section: Introductionmentioning

confidence: 99%

Protein-conformational diseases in childhood: Naturally-occurring hIAPP amyloid-oligomers and early β-cell damage in obesity and diabetes

Altamirano-Bustamante

Garrido‐Magaña

Moran

et al. 2020

PLoS ONE

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Background and aims This is the first time that obesity and diabetes mellitus (DM) as protein conformational diseases (PCD) are reported in children and they are typically diagnosed too late, when β-cell damage is evident. Here we wanted to investigate the level of naturally-ocurring or real (not synthetic) oligomeric aggregates of the human islet amyloid polypeptide (hIAPP) that we called RIAO in sera of pediatric patients with obesity and diabetes. We aimed to reduce the gap between basic biomedical research, clinical practice-health decision making and to explore whether RIAO work as a potential biomarker of early β-cell damage. Materials and methods We performed a multicentric collaborative, cross-sectional, analytical, ambispective and blinded study; the RIAO from pretreated samples (PTS) of sera of 146 pediatric patients with obesity or DM and 16 healthy children, were isolated, measured by sound indirect ELISA with novel anti-hIAPP cytotoxic oligomers polyclonal antibody (MEX1). We carried out morphological and functional studied and cluster-clinical data driven analysis.

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Fibrillation of human islet amyloid polypeptide and its toxicity to pancreatic β-cells under lipid environment

Cited by 6 publications

References 61 publications

Lipid Modulation in the Formation of β-Sheet Structures. Implications for De Novo Design of Human Islet Amyloid Polypeptide and the Impact on β-Cell Homeostasis

Lipid Modulation in the Formation of β-Sheet Structures. Implications for De Novo Design of Human Islet Amyloid Polypeptide and the Impact on β-Cell Homeostasis

Unpacking the aggregation-oligomerization-fibrillization process of naturally-occurring hIAPP amyloid oligomers isolated directly from sera of children with obesity or diabetes mellitus

Protein-conformational diseases in childhood: Naturally-occurring hIAPP amyloid-oligomers and early β-cell damage in obesity and diabetes

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