Endoplasmic reticulum stress induces inverse regulations of major functions in portal myofibroblasts during liver fibrosis progression

Loeuillard, Emilien; Mourabit, Haquima El; Lei, Lin; Lemoinne, Sara; Housset, Chantal; Cadoret, Axelle

doi:10.1016/j.bbadis.2018.10.008

Cited by 18 publications

(13 citation statements)

References 32 publications

(54 reference statements)

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“…For example, pathways that were enriched in the whole transcriptome analysis are related to ATF4 and PERK, which are each known to be upregulated in the presence of tunicamycin. 21,26,34,42,48 The downregulation of the "HALLMARK_ANGIOGENESIS" pathway is consistent with the inhibition of angiogenesis by tunicamycin in mice. 49 In addition, regulation by tunicamycin of Cytochrome P450 metabolism and N-glycan/N-linked glycosylation expression is supported by previous research findings.…”

Section: Gsea Pathway Analysissupporting

confidence: 65%

“…Tunicamycin is widely acknowledged to induce stress in the ER and activates the unfolded protein response (UPR) in many studies. 35,42,49 The “Unfolded protein response” keyword is also a small and specific category with only 11 measured genes and 35 measured + extrapolated genes. The additional 24 genes were necessary in this case to capture the significance of this keyword.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, a number of these additional DEGs are related to tunicamycin’s major biological response activities, as reported in the literature, of inducing stress in the ER and activating the UPR. 35,42,49 For example, the gene ERN1 (endoplasmic reticulum to nucleus signaling 1, also known as IRE1 ), which is among the extrapolated upregulated DEGs, encodes a protein responsible for triggering the most evolutionarily conserved branch in the UPR. 55 Overall, additional discoveries made possible by extrapolation contribute to a better understanding of the molecular changes caused by exposure to tunicamycin.…”

Section: Discussionmentioning

confidence: 99%

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Utility of Extrapolating Human S1500+ Genes to the Whole Transcriptome: Tunicamycin Case Study

Mav

Phadke

Balik-Meisner

et al. 2020

Bioinform Biol Insights

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The TempO-Seq S1500+ platform(s), now available for human, mouse, rat, and zebrafish, measures a discrete number of genes that are representative of biological and pathway co-regulation across the entire genome in a given species. While measurement of these genes alone provides a direct assessment of gene expression activity, extrapolating expression values to the whole transcriptome (~26 000 genes in humans) can estimate measurements of non-measured genes of interest and increases the power of pathway analysis algorithms by using a larger background gene expression space. Here, we use data from primary hepatocytes of 54 donors that were treated with the endoplasmic reticulum (ER) stress inducer tunicamycin and then measured on the human S1500+ platform containing ~3000 representative genes. Measurements for the S1500+ genes were then used to extrapolate expression values for the remaining human transcriptome. As a case study of the improved downstream analysis achieved by extrapolation, the “measured only” and “whole transcriptome” (measured + extrapolated) gene sets were compared. Extrapolation increased the number of significant genes by 49%, bringing to the forefront many that are known to be associated with tunicamycin exposure. The extrapolation procedure also correctly identified established tunicamycin-related functional pathways reflected by coordinated changes in interrelated genes while maintaining the sample variability observed from the “measured only” genes. Extrapolation improved the gene- and pathway-level biological interpretations for a variety of downstream applications, including differential expression analysis, gene set enrichment pathway analysis, DAVID keyword analysis, Ingenuity Pathway Analysis, and NextBio correlated compound analysis. The extrapolated data highlight the role of metabolism/metabolic pathways, the ER, immune response, and the unfolded protein response, each of which are key activities associated with tunicamycin exposure that were unrepresented or underrepresented in one or more of the analyses of the original “measured only” dataset. Furthermore, the inclusion of the extrapolated genes raised “tunicamycin” from third to first upstream regulator in Ingenuity Pathway Analysis and from sixth to second most correlated compound in NextBio analysis. Therefore, our case study suggests an approach to extend and enhance data from the S1500+ platform for improved insight into biological mechanisms and functional outcomes of diseases, drugs, and other perturbations.

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Section: Gsea Pathway Analysissupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Utility of Extrapolating Human S1500+ Genes to the Whole Transcriptome: Tunicamycin Case Study

Mav

Phadke

Balik-Meisner

et al. 2020

Bioinform Biol Insights

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“…Furthermore, ER stress was characterized by the accumulation of misfolded proteins (also known as the UPR) (Adams et al, 2019), and it could drive inflammatory signaling (Duvigneau et al, 2019) and be involved in the progression of liver disease (Loeuillard et al, 2018), including HCV-related liver disease (Chusri et al, 2016). UPR consisted of three branches of stress sensors: ATF6, IRE1-XBP1 and PERK, and UPR target gene included GRP78, CHOP, EDEM1, and p58 IPK et al (Loeuillard et al, 2018). These UPR target genes were notably increased in liver tissues from HCV patients with liver fibrosis, which was supported by previous findings (Koo et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Glutamate-Cysteine Ligase Catalytic Subunit Attenuated Hepatitis C Virus-Related Liver Fibrosis and Suppressed Endoplasmic Reticulum Stress

et al. 2020

Front. Mol. Biosci.

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The study aimed to clarify the role and molecular mechanism of glutamate-cysteine ligase catalytic subunit (GCLC) in modulating Hepatitis C virus (HCV)-related liver fibrosis. Twenty patients with HCV-related liver fibrosis and 15 healthy controls were enrolled. Differentially expressed plasma mRNAs were detected by digital gene expression profile analysis and validated by qRT-PCR. Hepatic histopathology was observed by H&E and Masson stained liver sections. The mRNA and protein expression of GCLC, endoplasmic reticulum (ER) stress markers, and inflammatory and fibrogenic factors were detected in liver tissues from patients with HCV-related hepatic fibrosis and HCV core protein-expressing LX-2. The GCLC-overexpressing LX-2 were established by transfecting puc19-GCLC plasmid. Then, glutathione and reactive oxygen species (ROS) levels were measured respectively by spectrophotometric diagnostic kit and dihydrodichlorofluorescein diacetate kit. GCLC were dramatically down-regulated in HCV-related fibrotic livers and activated HSCs, which companied with up-regulation of ER stress-related genes, including inositol-requiring 1 (IRE1) and glucose-regulated protein 78 (GRP78). Also, the proinflammatory and profibrogenic gene, including nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNFα), and transforming growth factor 1(TGFβ1), was highly upregulated. Overexpression of GCLC in hepatic stellate cells could suppress α-SMA and collagen I expression, produce hepatic GSH and reduce ROS, and down-regulate IRE1, GRP78, NF-κB, TNF-α, and TGFβ1 expression. GCLC was a negative regulatory factor in the development of HCV-related liver fibrosis and might be a potential therapeutic target for liver fibrosis.

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“…Prevents ER stress-induced enhancement of PERK and eIF2α phosphorylation as well as ATF4 & CHOP upregulation Inhibits M1 macrophage polarization (86). Decreases the angiogenesis ability of myofibroblast in liver fibrosis (138). Enhances glucose-stimulated insulin secretion (139).…”

Section: Gsk2656157mentioning

confidence: 99%

The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities

Song

Riesenberg

et al. 2020

Front. Immunol.

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The endoplasmic reticulum (ER) is an organelle equipped with mechanisms for proper protein folding, trafficking, and degradation to maintain protein homeostasis in the secretory pathway. As a defense mechanism, perturbation of ER proteostasis by ER stress agents activates a cascade of signaling pathways from the ER to the nucleus known as unfolded protein response (UPR). The primary goal of UPR is to induce transcriptional and translational programs to restore ER homeostasis for cell survival. As such, defects in UPR signaling have been implicated as a key contributor to multiple diseases including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer. Growing evidence support the critical role of ER stress in regulating the fate as well as the magnitude of the immune response. Moreover, the availability of multiple UPR pharmacological inhibitors raises the hope that targeting UPR can be a new strategy for immune modulation and immunotherapy of diseases. This paper reviews the principal mechanisms by which ER stress affects immune cell biology and function, with a focus of discussion on UPR-associated immunopathology and the development of potential ER stress-targeted therapeutics.Frontiers in Immunology | www.frontiersin.org Conflict of Interest: ZL serves as member of scientific advisory board for Alphamab and Henlius Biotech and has a sponsored research agreement with Bristol-Myers Squibb.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Endoplasmic reticulum stress induces inverse regulations of major functions in portal myofibroblasts during liver fibrosis progression

Cited by 18 publications

References 32 publications

Utility of Extrapolating Human S1500+ Genes to the Whole Transcriptome: Tunicamycin Case Study

Utility of Extrapolating Human S1500+ Genes to the Whole Transcriptome: Tunicamycin Case Study

Glutamate-Cysteine Ligase Catalytic Subunit Attenuated Hepatitis C Virus-Related Liver Fibrosis and Suppressed Endoplasmic Reticulum Stress

The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities

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