Global Liver Proteome Analysis Using iTRAQ Reveals AMPK–mTOR–Autophagy Signaling Is Altered by Intrauterine Growth Restriction in Newborn Piglets

Intrauterine growth restriction (IUGR)
impairs fetal growth and
development, perturbs nutrient metabolism, and increases the risk
of developing diseases in postnatal life. However, the underlying
mechanisms by which IUGR affects fetal liver development and metabolism
remain incompletely understood. Here, we applied a high-throughput
proteomics approach and biochemical analysis to investigate the impact
of IUGR on the liver of newborn piglets. As a result, we identified
78 differentially expressed proteins in the three biological replicates,
including 31 significantly up-regulated proteins and 47 significantly
down-regulated proteins. Among them, a majority of differentially
expressed proteins were related to nutrient metabolism and mitochondrial
function. Additionally, many significantly down-regulated proteins
participated in the mTOR signaling pathway and the phagosome maturation
signaling pathway. Further analysis suggested that glucose concentration
and hepatic glycogen storage were both reduced in IUGR newborn piglets,
which may contribute to AMPK activation and mTORC1 inhibition. However,
AMPK activation and mTORC1 inhibition failed to induce autophagy in
the liver of IUGR neonatal pigs. A possible reason is that PP2Ac,
a potential candidate in autophagy regulation, is significantly down-regulated
in the liver of IUGR newborn piglets. These findings may provide implications
for preventing and treating IUGR in human beings and domestic animals.

宫内生长受限（Intrauterine growth restriction, IUGR）可损害胎儿生长发育，扰乱营养代谢，并增加出生后罹患疾病的风险。然而，IUGR影响胎儿肝脏发育与代谢的潜在机制仍未完全阐明。本研究采用高通量蛋白质组学方法与生化分析技术，探究IUGR对新生仔猪肝脏的影响。结果在三组生物学重复样本中鉴定出78种差异表达蛋白，其中31种显著上调、47种显著下调。此类差异表达蛋白大多与营养代谢及线粒体功能相关。此外，大量显著下调的蛋白参与雷帕霉素靶蛋白（mTOR）信号通路与吞噬体成熟信号通路。进一步分析显示，IUGR新生仔猪的葡萄糖浓度与肝糖原储备均降低，这可能介导了腺苷酸活化蛋白激酶（AMPK）的激活与雷帕霉素靶蛋白复合物1（mTORC1）的抑制。但AMPK激活与mTORC1抑制并未诱导IUGR新生仔猪肝脏发生自噬。潜在原因之一是蛋白磷酸酶2A催化亚基（PP2Ac）——一种潜在的自噬调控候选分子——在IUGR新生仔猪肝脏中显著下调。本研究结果可为人类与家畜的IUGR防治提供理论参考。