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Vanadyl bisacetylacetonate protects β cells from palmitate-induced cell death through the unfolded protein response pathway

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Abstract

Endoplasmic reticulum (ER) stress induced by free fatty acids (FFA) is important to β-cell loss during the development of type 2 diabetes. To test whether vanadium compounds could influence ER stress and the responses in their mechanism of antidiabetic effects, we investigated the effects and the mechanism of vanadyl bisacetylacetonate [VO(acac)2] on β cells upon treatment with palmitate, a typical saturated FFA. The experimental results showed that VO(acac)2 could enhance FFA-induced signaling pathways of unfolded protein responses by upregulating the prosurvival chaperone immunoglobulin heavy-chain binding protein/78-kDa glucose-regulated protein and downregulating the expression of apoptotic C/EBP homologous protein, and consequently the reduction of insulin synthesis. VO(acac)2 also ameliorated FFA-disturbed Ca2+ homeostasis in β cells. Overall, VO(acac)2 enhanced stress adaption, thus protecting β cells from palmitate-induced apoptosis. This study provides some new insights into the mechanisms of antidiabetic vanadium compounds.

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Abbreviations

acac:

Acetylacetone

BiP/GRP78:

Immunoglobulin heavy-chain binding protein/78-kDa glucose-regulated protein

BSA:

Bovine serum albumin

cDNA:

Complementary DNA

CHOP:

C/EBP homologous protein

DCFH-DA:

2′,7′-Dichlorofluorescein diacetate

ER:

Endoplasmic reticulum

FBS:

Fetal bovine serum

FFA:

Free fatty acid

Fluo-3 AM:

1-[2-Amino-5-(2,7-dichloro-6-hydroxy-3-oxo-9-xanthenyl)phenoxy]-2-(2-amino-5-methylphenoxy)ethane-N,N,N′,N′-tetraacetic acid, pentaacetoxymethyl ester

HBSS:

N-(2-Hydroxyethyl)piperazine-N′-ethanesulfonic acid balanced salt solution

HEPES:

N-(2-Hydroxyethyl)piperazine-N′-ethanesulfonic acid

IRE1α:

Inositol-requiring enzyme 1α

mRNA:

Messenger RNA

MTT:

3-(4,5-Dimethylthiazoyl-2-yl)-2,5-diphenyltetrazolium bromide

PBS:

Phosphate-buffered saline

PERK:

Protein kinase regulated by RNA-like endoplasmic-reticulum-associated kinase

PI:

Propidium iodide

ROS:

Reactive oxygen species

TBS:

20 mM tris(hydroxymethyl)aminomethane–HCl, 1.37 mM NaCl, pH 7.6

TBST:

20 mM tris(hydroxymethyl)aminomethane–HCl, 1.37 mM NaCl, pH 7 containing 0.1% Tween 20

Tris:

Tris(hydroxymethyl)aminomethane

UPR:

Unfolded protein response

VO(acac)2 :

Vanadyl bisacetylacetonate

Xbp-1:

X-box binding protein 1

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Acknowledgments

This project (no. 20971008) was supported by the NSFC and the Research Fund for the Doctoral Program of Higher Education of China. We thank John J. Hefferren of the University of Kansas for editing the manuscript.

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Authors and Affiliations

  1. State Key Laboratories of Natural and Biomimetic Drugs and Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, People’s Republic of China

    Zhonglan Gao, Chengyue Zhang, Siwang Yu, Xiaoda Yang & Kui Wang

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  1. Zhonglan Gao
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  2. Chengyue Zhang
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  3. Siwang Yu
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  4. Xiaoda Yang
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  5. Kui Wang
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Correspondence to Siwang Yu or Xiaoda Yang.

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Gao, Z., Zhang, C., Yu, S. et al. Vanadyl bisacetylacetonate protects β cells from palmitate-induced cell death through the unfolded protein response pathway. J Biol Inorg Chem 16, 789–798 (2011). https://doi.org/10.1007/s00775-011-0780-0

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