Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes.
Interference with the HNF4-dependent gene regulatory network diminishes endoplasmic reticulum stress in hepatocytes.
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DOI：
10.1097/hc9.0000000000000278
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发表时间：
2023-11-01
影响因子：
5.1
通讯作者：
中科院分区：
文献类型：
--
作者：
在所有真核细胞类型中，未折叠蛋白反应（UPR）上调促进蛋白质折叠和错误折叠蛋白质清除的因子，以帮助缓解内质网（ER）应激。然而，肝脏中的ER应激独特地伴随着代谢基因的抑制，其协调和目的在很大程度上是未知的。在这里，我们结合了计算机机器学习，肝细胞分化主调节因子HNF 4 α的体内肝脏特异性缺失，以及肝细胞分化状态的体外操纵，以确定UPR如何调节肝细胞特性以及达到什么目的。机器学习确定了一组相关基因，这些基因被肝脏中持续的ER应激深深抑制。这些基因编码多种功能，包括代谢、凝血、药物解毒和胆汁合成，可能是肝细胞分化主调节因子HNF 4 α的靶点。这些基因对内质网应激的反应表现为肝脏特异性HNF 4 α缺失。引人注目的是，虽然HNF4α的缺失加重了对ER应激挑战的肝损伤，但它也减少了UPR活化并部分保留了ER超微结构，表明ER应激减弱。相反，在体外肝细胞特性的药理学维持增强了对应激的敏感性。总之，我们的研究结果表明，UPR通过HNF4α调节肝细胞特性，以保护ER稳态，即使以肝功能为代价。
In all eukaryotic cell types, the unfolded protein response (UPR) upregulates factors that promote protein folding and misfolded protein clearance to help alleviate endoplasmic reticulum (ER) stress. Yet, ER stress in the liver is uniquely accompanied by the suppression of metabolic genes, the coordination and purpose of which are largely unknown. Here, we combined in silico machine learning, in vivo liver-specific deletion of the master regulator of hepatocyte differentiation HNF4α, and in vitro manipulation of hepatocyte differentiation state to determine how the UPR regulates hepatocyte identity and toward what end. Machine learning identified a cluster of correlated genes that were profoundly suppressed by persistent ER stress in the liver. These genes, which encode diverse functions including metabolism, coagulation, drug detoxification, and bile synthesis, are likely targets of the master regulator of hepatocyte differentiation HNF4α. The response of these genes to ER stress was phenocopied by liver-specific deletion of HNF4α. Strikingly, while deletion of HNF4α exacerbated liver injury in response to an ER stress challenge, it also diminished UPR activation and partially preserved ER ultrastructure, suggesting attenuated ER stress. Conversely, pharmacological maintenance of hepatocyte identity in vitro enhanced sensitivity to stress. Together, our findings suggest that the UPR regulates hepatocyte identity through HNF4α to protect ER homeostasis even at the expense of liver function.
影响因子：
5.2
作者：
Ulianich L;Mirra P;Garbi C;Calì G;Conza D;Treglia AS;Miraglia A;Punzi D;Miele C;Raciti GA;Beguinot F;Consiglio E;Di Jeso B
通讯作者：
Di Jeso B
影响因子：
3.7
作者：
Arensdorf AM;Dezwaan McCabe D;Kaufman RJ;Rutkowski DT
通讯作者：
Rutkowski DT