Abstract

There is accumulating evidence showing that apoptosis induced by endoplasmic reticulum (ER) stress plays a key role in pancreatic β cell dysfunction and insulin resistance. 3β-Hydroxysteroid-Δ24 Reductase (DHCR24) is a multifunctional enzyme located in the endoplasmic reticulum (ER), which has been previously shown to protect neuronal cells from ER stress-induced apoptosis. However, the role of DHCR24 in type 2 diabetes is only incompletely understood so far. In the present study, we induced ER stress by tunicamycin (TM) treatment and showed that infection of MIN6 cells with Ad-DHCR24-myc rendered these cells resistant to caspase-3-mediated apoptosis induced by TM, while cells transfected with siRNAs targeting DHCR24 were more sensitive to TM. Western blot analysis showed that TM treatment induced upregulation of Bip protein levels in both cells infected with Ad-LacZ (the control group) and Ad-DHCR24-myc, indicating substantial ER stress. Cells infected with Ad-LacZ exhibited a rapid and strong activation of ATF6 and p38, peaking at 3 h after TM exposure. Conversely, cells infected with Ad-DHCR24-myc showed a higher and more sustained activation of ATF6 and Bip than control cells. DHCR24 overexpression also inhibited the generation of intracellular reactive oxygen species (ROS) induced by ER stress and protected cells from apoptosis caused by treatment with both cholesterol and hydrogen peroxide. In summary, these data demonstrate, for the first time, that DHCR24 protects pancreatic β cells from apoptosis induced by ER stress.

Highlights

  • Type 2 diabetes (T2D) is a metabolic disorder associated with a number of risk factors, including, amongst others, genetic factors, environmental exposure, obesity, and age [1, 2]

  • We have reported that DHCR24 exerts a reactive oxygen species (ROS)-scavenging effect and can attenuate apoptosis of mouse neuronal N2A cells and mouse embryonic fibroblast cells (MEFs) induced by endoplasmic reticulum (ER) stress and oxidative stress [22,23,24]

  • As DHCR24 catalyzes desmosterol to cholesterol during the last step of cholesterol biosynthesis, we investigated whether the intracellular cholesterol levels were affected by infection with Ad-LacZ or Ad-DHCR24-myc

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Summary

Introduction

Type 2 diabetes (T2D) is a metabolic disorder associated with a number of risk factors, including, amongst others, genetic factors, environmental exposure, obesity, and age [1, 2]. It is characterized by hyperglycemia due to the insufficient secretion of insulin, caused by a dysfunction of insulin-secreting pancreatic β cells, and decreased insulin sensitivity, caused by insulin resistance [3]. In T2D, hyperglycemia often occurs after β cells progressively fail to compensate for insulin resistance, and β cell failure is a crucial factor in the pathogenesis of T2D [4, 5]. In pancreatic tissues of patients with T2D, reduced cell mass has been observed [6, 7], and there is accumulating evidence that apoptosis is an important mechanism of β cell mass loss [6,7,8]. Therapeutic methods targeting and attenuating β cell apoptosis may be an effective method for the clinical management of T2D

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