Addition of exogenous sodium palmitate increases the IAPP/insulin mRNA ratio via GPR40 in human EndoC-βH1 cells

Krizhanovskii, Camilla; Fred, Rikard G.; Oskarsson, Marie E.; Westermark, Gunilla T.; Welsh, Nils

doi:10.1080/03009734.2017.1368745

Cited by 11 publications

(8 citation statements)

References 36 publications

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“…9 D ). EndoC-βH1 cells exposed to high SP and high glucose increase their IAPP secretion without a concomitant increase in insulin secretion ( 34 ). A scenario with high levels of IAPP in the secretory pathway with a concurrent reduction of antiamyloid chaperone Bri2 could be detrimental for the cells and induce cell death.…”

Section: Resultsmentioning

confidence: 99%

BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells

Oskarsson

Hermansson

Wang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceAccumulation of islet amyloid polypeptide (IAPP)-containing amyloid fibrils is the main pathological finding in pancreatic islets in type 2 diabetes. The formation of these IAPP amyloid fibrils is considered toxic and may constitute a major cause for the loss of insulin-producing beta cells. The protein domain BRICHOS is present in several different proproteins and possesses antiamyloid chaperone activity. This study demonstrates expression of the BRICHOS-containing protein Bri2 in human pancreatic beta cells and its colocalization with IAPP. The Bri2 BRICHOS domain effectively prevents IAPP from forming fibrils and protects cells from the toxicity associated with IAPP fibrillation. It is concluded that the Bri2 BRICHOS domain may act as an endogenous inhibitor of IAPP amyloid formation in pancreatic beta cells.

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Section: Resultsmentioning

confidence: 99%

BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells

Oskarsson

Hermansson

Wang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…The generation of such hybrid fusion peptides is energetically unfavorable and also requires precise joining of two proteolytic fragments in the presence of competing peptide fragments. The C-terminal fragment of 6.9HIP originates from islet amyloid polypeptide, which is present at a level of ∼1% compared with insulin (Krizhanovskii et al, 2017). It therefore appears likely that hybrid fusion peptides are produced by β cells in small quantities.…”

Section: Discussionmentioning

confidence: 99%

Rapid CLIP dissociation from MHC II promotes an unusual antigen presentation pathway in autoimmunity

Ito

Ashenberg

Pyrdol

et al. 2018

Journal of Experimental Medicine

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A number of autoimmunity-associated MHC class II proteins interact only weakly with the invariant chain-derived class II-associated invariant chain peptide (CLIP). CLIP dissociates rapidly from I-A even in the absence of DM, and this property is related to the type 1 diabetes-associated β57 polymorphism. We generated knock-in non-obese diabetic (NOD) mice with a single amino acid change in the CLIP segment of the invariant chain in order to moderately slow CLIP dissociation from I-A These knock-in mice had a significantly reduced incidence of spontaneous type 1 diabetes and diminished islet infiltration by CD4 T cells, in particular T cells specific for fusion peptides generated by covalent linkage of proteolytic fragments within β cell secretory granules. Rapid CLIP dissociation enhanced the presentation of such extracellular peptides, thus bypassing the conventional MHC class II antigen-processing pathway. Autoimmunity-associated MHC class II polymorphisms therefore not only modify binding of self-peptides, but also alter the biochemistry of peptide acquisition.

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“…Previous studies have reported decreased insulin content in rodent and human pancreatic beta-cells after palmitate treatment (32, 33), with evidence that the mechanism involves decreased insulin translation (33). As shown in Fig 5B, palmitate decreased insulin content in both Pex11 β knock down and control cells at high glucose, but this was less pronounced in the Pex11 β knock down cells.…”

Section: Discussionmentioning

confidence: 99%

Pex11β knockdown decreases peroxisome abundance and reverses the inhibitory effect of palmitate on pancreatic beta-cell function

Walker

Blair

Brown

et al. 2020

Preprint

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12 13 14 *Corresponding Author: 15 Mark.walker@ncl.ac.uk 16 2 17 Aims18 Reactive oxygen species generated by the peroxisomes and mitochondria contribute to 19 lipotoxicity in pancreatic beta-cells. Through targeted Pex11β knockdown and peroxisome 20 depletion, our aim was to investigate the specific contribution of peroxisomes to palmitate 21 mediated pancreatic beta-cell dysfunction.22 Methods 23 MIN6 cells were transfected with probes targeted against Pex11β, a regulator of peroxisome 24 abundance, or with scrambled control probes. Peroxisome abundance was measured by 25 PMP-70 protein expression. 48hrs post transfection, cells were incubated with or without 26 250μM palmitate for a further 48hrs before measurement of reactive oxygen species, 27 mitochondrial respiratory function, and glucose stimulated insulin secretion. Results29 Pex11β knockdown decreased target gene expression by more than 80% compared with the 30 scrambled control (P<0.001), leading to decreased PMP-70 expression (p<0.01). Pex11β 31 knockdown decreased palmitate mediated generation of reactive oxygen species (P<0.001), 32 but with no effect on mitochondrial respiratory function. At 25mM glucose, palmitate 33 treatment decreased insulin secretion in the control cells (2.54±0.25 vs 7.07±0.83 34 [mean±SEM] ng/hr/µg protein; P<0.001), with a similar pattern in the Pex11β knockdown 35 cells. However, in the presence of palmitate, insulin secretion was significantly higher in the 36 Pex11β knockdown versus control cells (4.04±0.46 vs 2.54±0.25 ng/hr/µg protein; p<0.05). Conclusion38 Pex11β knockdown decreased peroxisome abundance, decreased palmitate mediated ROS 39 generation, and reversed the inhibitory effect of palmitate on insulin secretion. These 40 findings highlight a specific and independent role for peroxisomes in pancreatic beta-cell 41 lipotoxicity. 42 43 44 3 45 46 Introduction47 Increased adiposity is a risk factor for type 2 diabetes. Ectopic fat deposition arises when 48 excess lipid is stored in tissues other than adipose tissue, such as the liver, muscle and 49 pancreas. Lipid excess in the pancreas is associated with pancreatic beta-cell dysfunction 50 and impaired insulin secretion (1-4). In vitro, chronic treatment with the long chain 51 saturated fatty acid palmitate has been shown to reduce insulin secretion in human, rat and 52 mouse islets (5-7) and pancreatic beta-cell lines (7-10). 53 Fatty acid β-oxidation in animals and man is conducted by both peroxisomes and 54 mitochondria (11, 12). Peroxisomes have a role in β-oxidation of long and medium chain 55 fatty acids, with the intermediate products transported to the mitochondria for complete 56 oxidation (12, 13). The first step of peroxisomal β-oxidation generates reactive oxygen 57 species (ROS), principally hydrogen peroxide (H 2 O 2 ). In the majority of cells, this is 58 catabolised by oxidoreductase catalase. However, pancreatic β-cells are essentially deficient 59 in this enzyme (14-16) leaving them at risk of lipotoxicity from excess H 2 O 2 production. 60 Elsne...

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Addition of exogenous sodium palmitate increases the IAPP/insulin mRNA ratio via GPR40 in human EndoC-βH1 cells

Cited by 11 publications

References 36 publications

BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells

BRICHOS domain of Bri2 inhibits islet amyloid polypeptide (IAPP) fibril formation and toxicity in human beta cells

Rapid CLIP dissociation from MHC II promotes an unusual antigen presentation pathway in autoimmunity

Pex11β knockdown decreases peroxisome abundance and reverses the inhibitory effect of palmitate on pancreatic beta-cell function

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