The unfolded protein response (UPR) is an adaptive response that is implicated in multiple metabolic pathologies, including hepatic steatosis. In the present study, we analyzed publicly available RNAseq data to explore how the execution of the UPR is orchestrated in specimens that exhibit hepatocyte ballooning, a landmark feature of steatosis. By focusing on a panel of well-established UPR genes, we assessed how the UPR is coordinated with the whole transcriptome in specimens with or without hepatocyte ballooning. Our analyses showed that neither average levels nor correlation in expression between major UPR genes such as HSPA5 (BiP/GRP78), HSP90b1 (GRP94), or DDIT3 (CHOP) is altered in different groups. However, a panel of transcripts depending on the stringency of the analysis ranged from 16 to 372 lost its coordination with HSPA5, the major UPR chaperone, when hepatocyte ballooning occurred. In 13 genes, the majority of which is associated with metabolic processes, and the coordination with the HSPA5 was reversed from positive to negative in livers with ballooning hepatocytes. In order to examine if during ballooning, UPR genes abolish established and acquire novel functionalities, we performed gene ontology analyses. These studies showed that among the various UPR genes interrogated, only DDIT3 was not associated with conventional functions linked to endoplasmic reticulum stress during ballooning, while HSPA90b1 exhibited the highest function retention between the specimens with or without ballooning. Our results challenge conventional notions on the impact of specific genes in disease and suggest that besides abundance, the mode of coordination of UPR may be more important for disease development.

未折叠蛋白反应（UPR）是一种适应性反应，与多种代谢病理学有关，包括肝脂肪变性。在本研究中，我们分析了公开的 RNAseq 数据，以探索如何在表现出肝细胞膨胀（脂肪变性的一个标志性特征）的样本中协调 UPR 的执行。通过关注一组成熟的 UPR 基因，我们评估了在有或没有肝细胞气球样变的样本中 UPR 如何与整个转录组协调。我们的分析表明，主要 UPR 基因（例如 HSPA5 (BiP/GRP78)、HSP90b1 (GRP94) 或 DDIT3 (CHOP)）之间的表达平均水平和相关性在不同组中均没有改变。然而，当肝细胞膨胀时，根据分析的严格程度，一组从 16 到 372 不等的转录本失去了与 HSPA5（主要 UPR 伴侣）的协调。在 13 个基因中，其中大部分与代谢过程相关，在肝细胞膨胀的肝脏中，与 HSPA5 的协调从阳性逆转为阴性。为了检查在气球膨胀过程中，UPR 基因是否会废除已建立的并获得新的功能，我们进行了基因本体分析。这些研究表明，在所研究的各种 UPR 基因中，只有 DDIT3 与气球膨胀过程中内质网应激相关的常规功能无关，而 HSPA90b1 在有或没有气球膨胀的样本之间表现出最高的功能保留。我们的结果挑战了关于特定基因对疾病影响的传统观念，并表明除了丰度之外，UPR 的协调模式可能对疾病的发展更为重要。