Coordination of the unfolded protein response during hepatic steatosis identifies CHOP as a specific regulator of hepato
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ORIGINAL PAPER
Coordination of the unfolded protein response during hepatic steatosis identifies CHOP as a specific regulator of hepatocyte ballooning Y. Zhang 1 & I. Chatzistamou 2 & H. Kiaris 1,3 Received: 28 April 2020 / Revised: 28 April 2020 / Accepted: 17 June 2020 # Cell Stress Society International 2020
Abstract 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 wellestablished 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. Keywords Liver . ER stress . Correlation network . Pathogenesis
Introduction During an individual’s lifetime and in response to certain environmental and other challenges, the cells continuously adapt Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12192-020-01132-x) contains supplementary material, which is available to authorized users. * H. Kiaris [email protected] 1
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, CLS 713, 715 Sumter St, Columbia, SC, USA
2
Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, USA
3
Peromyscus Genetic Stock Center, University of South Carolina, CLS 713, 715 Sumter St, Columbia, SC, USA
their transcriptional program in order to attain homeostasis, adequate physiological performance, and normal function (van Dam et al. 2018). In disease, homeostasis is abolished, and this is associated with organ dysfu
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