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Published on: September 9, 2021
Peroxisome Deficiency Dysregulates Fatty Acid Oxidization and Exacerbates Lipotoxicity in β Cells
Hongbo Guan1, Yanyan Guo1, Liangliang Zhu1
1Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China.
Insights
Reduced Pex14 protein impairs pancreatic beta cell function and survival by disrupting peroxisomes. This leads to increased oxidative stress and inflammation, exacerbating fatty acid toxicity in beta cells.
Area of Science:
- Endocrinology
- Cell Biology
- Metabolic Research
Background:
- Adverse intrauterine environments can lead to fetal pancreatic islet developmental issues, resulting in insufficient beta cell mass and function.
- Pex14, a key protein in peroxisome biogenesis and degradation, is notably reduced in fetuses with intrauterine growth restriction and persists into adulthood.
- Peroxisomes are crucial for metabolic processes, including fatty acid oxidation, reactive oxygen species (ROS) detoxification, and anti-inflammatory responses.
Purpose of the Study:
- To investigate the impact of Pex14 gene downregulation on pancreatic beta cell function and viability.
- To elucidate the role of Pex14 in regulating peroxisomal function, metabolic processes, and cellular stress responses within beta cells.
Main Methods:
- Pex14 was knocked down using small interfering RNA (siRNA) in INS-1 rat insulinoma cells.
- Assessed peroxisomal biogenesis, fatty acid metabolism, lipid storage, ROS levels, insulin secretion, inflammation factors, and endoplasmic reticulum stress markers.
- Evaluated the exacerbation of fatty acid lipotoxicity, including H2O2 accumulation and programmed cell death.
Main Results:
- Pex14 knockdown disrupted peroxisomal biogenesis and dysregulated fatty acid metabolism and lipid storage.
- Knockdown led to increased ROS levels, blunted insulin secretion, and upregulated inflammation and endoplasmic reticulum stress markers.
- The lipotoxicity of fatty acids (palmitic and linoleic acid) in beta cells was significantly exacerbated by Pex14 knockdown, evidenced by increased H2O2 and cell death.
Conclusions:
- Pex14 plays a vital role in maintaining normal peroxisome function and pancreatic beta cell viability.
- Functional peroxisomal metabolism is essential for detoxifying excess fatty acids in beta cells, preventing lipotoxicity and dysfunction.
- Downregulation of Pex14 contributes to beta cell impairment, highlighting its significance in conditions arising from adverse intrauterine environments.
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.
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