Maternal protein deficiency impairs peroxisome biogenesis and leads to oxidative stress and ferroptosis in liver of fetal growth restriction offspring
Maternal protein deficiency impairs peroxisome biogenesis and leads to oxidative stress and ferroptosis in liver of fetal growth restriction offspring
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DOI：
10.1016/j.jnutbio.2023.109432
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发表时间：
2023-09-04
影响因子：
5.6
通讯作者：
Liu，Xiaomei
中科院分区：
文献类型：
--
作者：
Guo，Yanyan;Zhou，Pei;Liu，Xiaomei
母体蛋白质营养不良会导致肝功能障碍，增加成年胎儿生长受限(FGR)子代患非酒精性脂肪性肝病的易感性，但其潜在机制尚不清楚。过氧化物酶体在脂肪酸β氧化(FAO)和活性氧物种(ROS)的解毒中起着重要作用。使用定义明确的大鼠模型，研究了FGR子代肝脏中的过氧化物素(PEXs)、脂肪酸代谢酶和氧化应激调节剂。结果表明，PEX3、11b、14和19在胎肝中明显减少，并持续到成年期，提示过氧化物体的生物发生和分裂减少。脂肪酸代谢酶和铁下垂调节剂被解除调控。为了进一步研究这种关联，利用小干扰RNA在BRL细胞(一种大鼠肝细胞系)中实现了PEX14的敲除(KD)。PEX14 kD导致PEXs表达失调和长链脂肪酸蓄积。PEX14缺乏导致ROS积聚和脂质过氧化，最终诱导调节性T细胞死亡(包括细胞凋亡、自噬和铁下垂)。PEX14和脂肪酰辅酶A还原酶1(FAR1)的双重敲除(DKD)显示PEX14 KD诱导的铁下垂与FAR1水平升高有关。PEX14和ATG5的DKD进一步证实了PEX14 KD诱导的细胞死亡部分依赖于自噬。总体而言，这些数据表明PEX14在维持过氧化体功能和肝脏生理方面发挥了至关重要的作用，并表明肝细胞过氧化酶体缺陷在一定程度上解释了胎儿原发肝病中肝脏发育不良和脂代谢紊乱的原因。
Maternal protein malnutrition leads to liver dysfunction and increases susceptibility to nonalcoholic fatty liver disease in adult fetal growth restriction (FGR) offspring, yet the underlying mechanism remains unknown. Peroxisomes play vital roles in fatty acid β-oxidation (FAO) and detoxification of reactive oxygen species (ROS). Using a well-defined rat model, the peroxins (PEXs), fatty acid metabolic enzymes, and oxidase stress regulators were investigated in the liver of FGR offspring. The results revealed that PEX3, 11b, 14, and 19 were obviously reduced in the fetal liver and lasted to adulthood, suggesting a decrease in the biogenesis and division of peroxisomes. FA metabolism enzymes and ferroptosis regulators were deregulated. To further investigate this association, small interfering RNA was employed to achieve knockdown (KD) of PEX14 in BRL cells (a rat hepatocyte line). PEX14 KD led to dysregulation of PEXs and long-chain FAs accumulation. PEX14 deficiency caused ROS accumulation and lipid peroxidation, finally induced regulated cell death (including apoptosis, autophagy, and ferroptosis). Double knock down (DKD) of PEX14 and fatty acyl-CoA reductase 1 (FAR1) revealed that PEX14 KD-induced ferroptosis was related with enhanced FAR1 level. DKD of PEX14 and Atg5 further confirmed that PEX14 KD-induced cell death was partly autophagy-dependent. Overall, these data demonstrate a vital role for PEX14 in maintaining peroxisome function and liver physiology, and suggest that hepatocyte peroxisome defects partly explain liver dysplasia and lipid metabolism disorders in fetal original liver disease.