Peroxisome Deficiency Dysregulates Fatty Acid Oxidization and Exacerbates Lipotoxicity in β Cells.

Hongbo Guan,Xiaomei Liu,Yanyan Guo,Yisheng Jiao,Liangliang Zhu

doi:10.1155/2021/7726058

Hongbo Guan, Xiaomei Liu + Show 3 more

Open Access

https://doi.org/10.1155/2021/7726058

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Abstract

An adverse intrauterine environment impairs the development of pancreatic islets in the fetus and leads to insufficient β cell mass and β cell dysfunction. We previously reported that Pex14, a peroxin protein involved in the biogenesis and degradation of peroxisomes, is markedly reduced in the pancreas of an intrauterine growth restriction fetus and last into adulthood. Peroxisomes function in a wide range of metabolic processes including fatty acid oxidization, ROS detoxification, and anti-inflammatory responses. To elucidate the impact of downregulation of the Pex14 gene on β cell, Pex14 was knocked down by siRNA in INS-1 cells. Pex14 knockdown disturbed peroxisomal biogenesis and dysregulated fatty acid metabolism and lipid storage capability, thereby increased ROS level and blunted insulin secretion. Moreover, Pex14 knockdown upregulated inflammation factors and regulators of endoplasmic reticulum stress. The lipotoxicity of fatty acid (including palmitic acid and linoleic acid) in β cells was exacerbated by knockdown of Pex14, as indicated by H2O2 accumulation and increased programmed cell death. The present results demonstrate the vital role of Pex14 in maintaining normal peroxisome function and β cell viability and highlight the importance of a functional peroxisomal metabolism for the detoxification of excess FAs in β cells.

Highlights

The peroxisome is an organelle with multiple biological functions that is widely present in mammalian cells
In this study, using siRNA to knock down the expression of Pex14, we found that downregulation of Pex14 induced β cell death and damaged insulin secretion function by affecting multiple proteins involved in peroxisome biogenesis, FA β-oxidation (FAO), and reactive oxygen species (ROS) scavenging, subsequently leading to cell autophagy and apoptosis
The mRNA level of Pex3 and Pex5 was upregulated by Pex14 KD which was inconsistent with the protein data (Figure 1(e))

Summary

Introduction

The peroxisome is an organelle with multiple biological functions that is widely present in mammalian cells. The first is constitutive proteins, called peroxins (PEX), which interact with each other and participate in peroxisome biogenesis, division, and proliferation. Peroxisomes are involved in a wide variety of metabolic pathways such as β-oxidization of very-longchain fatty acids (VLCFAs), α-oxidization and β-oxidization of long branched-chain fatty acids (FAs), phospholipid synthesis, reactive oxygen species (ROS) metabolism, and antiinflammatory functions [3,4,5]. PEX gene mutations cause defects in peroxisome production and loss of mature peroxisomes, leading to a group of diseases known as peroxisomal biogenesis disease [2]. The underlying pathological mechanism involves impaired oxidization of VLCFAs, which accumulate in the cytoplasm, affecting cell function and embryo development [6, 7]. The imbalance between the two processes causes oxidative stress (OS) [8]

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