Cell death‐inducing DFF45‐like effector b (Cideb) is present in pancreatic beta‐cells and involved in palmitate induced beta‐cell apoptosis

Li, H.; Song, Yong; Zhang, L. J.; Li, F. F.; Gu, Yu; Zhang, J.; Dong, Wenfang; Li, Xue; Liu, Fei; Wang, J.; Jiang, Lina; Ye, J.; Li, Q.

doi:10.1002/dmrr.1295

Cited by 14 publications

(10 citation statements)

References 40 publications

(110 reference statements)

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“…The involvement of other NEFA-dependent signals in the promotion of beta cell dysfunction and death has also been proposed. These include activation of Erk-1/2 [32], NF-κB [33], protein-kinase C (PKC)-δ [34], endoplasmic reticulum (ER) stress [35], calpain-10 [36] and ceramide formation [37], and induction of sterol regulatory element-binding protein [38], macrophage migration inhibitory factor [39], cell death-inducing DNA fragmentation factor a-like effector A [40] and cell death-inducing DFF45-like effector b [41]. NEFA-mediated inhibition of Akt activity [42] has also been implicated.…”

Section: Discussionmentioning

confidence: 99%

Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway

et al. 2013

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Aims/hypothesis The mechanisms of the protective effects of exendin-4 on NEFA-induced beta cell apoptosis were investigated. Methods The effects of exendin-4 and palmitate were evaluated in human and murine islets, rat insulin-secreting INS-1E cells and murine glucagon-secreting alpha-TC1-6 cells. mRNA and protein expression/phosphorylation were measured by real-time RT-PCR and immunoblotting or immunofluorescence, respectively. Small interfering (si)RNAs for Ib1 and Gpr40 were used. Cell apoptosis was quantified by two independent assays. Insulin release was assessed with an insulin ELISA. Results Exposure of human and murine primary islets and INS-1E cells, but not alpha-TC1-6 cells, to exendin-4 inhibited phosphorylation of the stress kinases, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), and prevented apoptosis in response to palmitate. Exendin-4 increased the protein content of islet-brain 1 (IB1), an endogenous JNK blocker; however, siRNA-mediated reduction of IB1 did not impair the ability of exendin-4 to inhibit JNK and prevent apoptosis. Exendin-4 reduced G-protein-coupled receptor 40 (GPR40) expression and inhibited palmitateinduced phosphorylation of mitogen-activated kinase kinase (MKK)4 and MKK7. The effects of exendin-4 were abrogated in the presence of the protein kinase A (PKA) inhibitors, H89 and KT5720. Knockdown of GPR40, as well as use of a specific GPR40 antagonist, resulted in diminished palmitateinduced JNK and p38 MAPK phosphorylation and apoptosis. Furthermore, inhibition of JNK and p38 MAPK activity prevented palmitate-induced apoptosis. Conclusions/interpretation Exendin-4 counteracts the proapoptotic effects of palmitate in beta cells by reducing GPR40 expression and inhibiting MKK7-and MKK4-dependent phosphorylation of the stress kinases, JNK and p38 MAPK, in a PKA-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway

et al. 2013

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“…Visualization was performed using 0.1% 3,3'-diaminobenzidine (Dako, Denmark) in PBS together with 0.05% H 2 O 2 (ref. 47 ). For the analysis of CLS, immunohistochemistry sections stained with a TNFα antibody were used and the CLS density was derived by counting the total number of CLS in each section compared with the total number of adipocytes.…”

Section: Methodsmentioning

confidence: 99%

Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice

Zhou

Park

et al. 2015

Nat Commun

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Fsp27 is a lipid droplet-associated protein almost exclusively expressed in adipocytes where it facilitates unilocular lipid droplet formation. In mice, Fsp27 deficiency is associated with increased basal lipolysis, ‘browning’ of white fat and a healthy metabolic profile, whereas a patient with congenital CIDEC deficiency manifested an adverse lipodystrophic phenotype. Here we reconcile these data by showing that exposing Fsp27-null mice to a substantial energetic stress by crossing them with ob/ob mice or BATless mice, or feeding them a high-fat diet, results in hepatic steatosis and insulin resistance. We also observe a striking reduction in adipose inflammation and increase in adiponectin levels in all three models. This appears to reflect reduced activation of the inflammasome and less adipocyte death. These findings highlight the importance of Fsp27 in facilitating optimal energy storage in adipocytes and represent a rare example where adipose inflammation and hepatic insulin resistance are disassociated.

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“…Palmitate also impairs glucose-stimulated insulin secretion and β-cell function in rat insulin-secreting INS-1 cells [46] and induces H 2 O 2 formation in the peroxisomes of RINm5F insulin-producing cells [47], showing its lipotoxicity in vitro. Furthermore, palmitate exposure may induce apoptosis in isolated islets from humans [43,48], possibly through its receptor cell death-inducing DFF45-like effector b (Cideb) [48]. Oxidative stress is another negative effect under palmitate exposure, accompanied with apoptosis in βTC6 cells (a glucose-sensitive mouse β pancreatic cell line) through activating free fatty acid receptor 1 (FFAR1) [49].…”

Section: Direct Dangerous Factors Under High Fructose Consumptionmentioning

confidence: 99%

High Dietary Fructose: Direct or Indirect Dangerous Factors Disturbing Tissue and Organ Functions

2017

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High dietary fructose is a major contributor to insulin resistance and metabolic syndrome, disturbing tissue and organ functions. Fructose is mainly absorbed into systemic circulation by glucose transporter 2 (GLUT2) and GLUT5, and metabolized in liver to produce glucose, lactate, triglyceride (TG), free fatty acid (FFA), uric acid (UA) and methylglyoxal (MG). Its extrahepatic absorption and metabolism also take place. High levels of these metabolites are the direct dangerous factors. During fructose metabolism, ATP depletion occurs and induces oxidative stress and inflammatory response, disturbing functions of local tissues and organs to overproduce inflammatory cytokine, adiponectin, leptin and endotoxin, which act as indirect dangerous factors. Fructose and its metabolites directly and/or indirectly cause oxidative stress, chronic inflammation, endothelial dysfunction, autophagy and increased intestinal permeability, and then further aggravate the metabolic syndrome with tissue and organ dysfunctions. Therefore, this review addresses fructose-induced metabolic syndrome, and the disturbance effects of direct and/or indirect dangerous factors on the functions of liver, adipose, pancreas islet, skeletal muscle, kidney, heart, brain and small intestine. It is important to find the potential correlations between direct and/or indirect risk factors and healthy problems under excess dietary fructose consumption.

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Cell death‐inducing DFF45‐like effector b (Cideb) is present in pancreatic beta‐cells and involved in palmitate induced beta‐cell apoptosis

Abstract: The present results suggest that increased Cideb expression upon palmitate exposure may be involved in beta cell lipoapoptosis through its influence on conversion of FFAs to lipid esters in lipid droplets.

Cited by 14 publications

References 40 publications

Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway

Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway

Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice

High Dietary Fructose: Direct or Indirect Dangerous Factors Disturbing Tissue and Organ Functions

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