Peroxisome Deficiency Dysregulates Fatty Acid Oxidization and Exacerbates Lipotoxicity in β Cells.
Peroxisome Deficiency Dysregulates Fatty Acid Oxidization and Exacerbates Lipotoxicity in β Cells.
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DOI：
10.1155/2021/7726058
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发表时间：
2021
影响因子：
--
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Guan H;Guo Y;Zhu L;Jiao Y;Liu X
不利的宫内环境会损害胎儿胰岛的发育，并导致β细胞量不足和β细胞功能障碍。我们以前报道过，Pex 14，过氧化物酶体的生物合成和降解的过氧化物酶蛋白，是显着减少，在胰腺的宫内生长受限胎儿，并持续到成年。过氧化物酶体在广泛的代谢过程中起作用，包括脂肪酸氧化、ROS解毒和抗炎反应。为探讨Pex 14基因下调对β细胞的影响，采用siRNA敲除INS-1细胞中的Pex 14基因。Pex 14敲低干扰过氧化物酶体的生物合成和失调的脂肪酸代谢和脂质储存能力，从而增加ROS水平和钝化胰岛素分泌。此外，Pex 14敲低上调炎症因子和内质网应激调节因子。Pex 14基因敲减可加重β细胞中脂肪酸（包括棕榈酸和亚油酸）的脂毒性，如H2 O2蓄积和程序性细胞死亡增加所示。目前的结果表明Pex 14在维持正常过氧化物酶体功能和β细胞活力方面的重要作用，并强调了功能性过氧化物酶体代谢对β细胞中过量FA解毒的重要性。
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.
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