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Coordination of the unfolded protein response during hepatic steatosis identifies CHOP as a specific regulator of hepatocyte ballooning

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Cell Stress and Chaperones Aims and scope

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 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.

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Funding

This study was supported by NSF (Award Number: 1736150).

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Authors and Affiliations

  1. Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, CLS 713, 715 Sumter St, Columbia, SC, USA

    Y. Zhang & H. Kiaris

  2. Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, USA

    I. Chatzistamou

  3. Peromyscus Genetic Stock Center, University of South Carolina, CLS 713, 715 Sumter St, Columbia, SC, USA

    H. Kiaris

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  1. Y. Zhang
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YZ performed the analyses, interpreted results, and edited and approved MS; IC interpreted the results and edited and approved MS; and HK analyzed the data, interpreted the results, and drafted and approved MS.

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Correspondence to H. Kiaris.

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Zhang, Y., Chatzistamou, I. & Kiaris, H. Coordination of the unfolded protein response during hepatic steatosis identifies CHOP as a specific regulator of hepatocyte ballooning. Cell Stress and Chaperones 25, 969–978 (2020). https://doi.org/10.1007/s12192-020-01132-x

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