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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 3  |  Issue : 4  |  Page : 80-82

The primary unfolded protein response transducer endoplasmic reticulum-to-nucleus signaling 1 is downregulated in livers of human nonalcoholic steatohepatitis patients


1 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
2 Center for Molecular Medicine and Genetics; Department of Biochemistry, Microbiology, and Immunology; Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

Date of Submission06-Jan-2019
Date of Acceptance07-Jan-2019
Date of Web Publication25-Jan-2019

Correspondence Address:
Kezhong Zhang
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 540 E. Canfield Avenue, Detroit, MI 48201
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ed.ed_1_19

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  Abstract 


Background: The Unfolded Protein Response (UPR) is an elegant signaling pathway from the Endoplasmic Reticulum (ER) to protect cells from stress caused by accumulation of unfolded or misfolded proteins in the ER lumen. ER-to-Nucleus Signaling 1 (IRE1, also called ERN1), an ER-localized protein kinase and endoribonuclease (RNase), is the most conserved transducer of the UPR signaling pathway. In this study, we investigated expression levels of IRE1 in the livers of human non-alcoholic steatohepatitis (NASH) patients.
Methods: We analyzed the expression profiles of the primary UPR transducer IRE1 in the livers of human NASH patients based on the microarray gene expression datasets obtained from public domain.
Results: Our analyses indicated that expression levels of IRE1 were decreased in the livers of human obese patients with NASH, compared to those of obese patients without NASH.
Conclusions: Our analysis result is consistent with the role of IRE1-mediated UPR in preserving cellular homeostasis and functions and in protecting organisms from injuries. This study provides important information in regard to the activation and functional involvement of the UPR signaling pathway in human NASH.

Keywords: Endoplasmic reticulum stress, unfolded protein response, IRE1, non-alcoholic steatohepatitis.


How to cite this article:
Shamsa E, Zhang K. The primary unfolded protein response transducer endoplasmic reticulum-to-nucleus signaling 1 is downregulated in livers of human nonalcoholic steatohepatitis patients. Environ Dis 2018;3:80-2

How to cite this URL:
Shamsa E, Zhang K. The primary unfolded protein response transducer endoplasmic reticulum-to-nucleus signaling 1 is downregulated in livers of human nonalcoholic steatohepatitis patients. Environ Dis [serial online] 2018 [cited 2022 Dec 3];3:80-2. Available from: http://www.environmentmed.org/text.asp?2018/3/4/80/250874




  Introduction Top


The endoplasmic reticulum (ER) is an intracellular organelle where proteins destined for the extracellular space, plasma membrane, and the exo/endocytic compartments are folded and assembled.[1],[2],[3] ER stress, represented by the accumulation of unfolded or misfolded proteins in the ER lumen, is known to induce the unfolded protein response (UPR), an intracellular stress signaling pathway from the ER which alters transcriptional and translational programs within stressed cells. A number of biochemical stimuli or pathophysiological processes, such as perturbation in calcium homeostasis, elevated secretory protein synthesis, overloading of cholesterol or lipids, hyperhomocysteinemia, nutrient deprivation, or infection with pathogenic organisms, can disrupt ER homeostasis and subsequently lead to UPR activation.[3],[4] The UPR is orchestrated by transcriptional activation of multiple genes that are mediated by the protein kinase/endoribonuclease IRE1 (ER-to-nucleus signaling 1, also called ERN1), the b-ZiP transcription factor ATF6 (activating transcription factor 6), a general decrease in translation initiation, and the selective translation of specific mRNAs mediated by the protein kinase PERK (PKR-like ER kinase).[1],[5] In particular, IRE1, the most conserved transducer of UPR signaling, plays a key role in aiding cells to adapt to and survive ER stress conditions. Indeed, IRE1 has been implicated in many physiological processes and the development of complex human diseases.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is considered the hepatic manifestation of metabolic syndrome.[6],[7] NAFLD is characterized by excessive hepatic lipid accumulation in the absence of significant ethanol consumption, viral infection, or other specific etiologies. Nonalcoholic steatohepatitis (NASH), the advanced stage of NAFLD, is found in a substantial fraction of individuals with fatty livers who develop chronic cell injury due to excess lipid deposition.[7] The livers of NASH patients exhibit hepatic inflammation, fibrosis, and liver cell death in addition to steatosis. In recent years, the functional involvement of ER stress and UPR in NAFLD has been largely studied. However, there is controversy in regard to whether the UPR signaling is upregulated or downregulated in the livers of NAFLD or NASH patients or animal models. In this study, we investigated the expression profiles of the primary UPR transducer IRE1 in the livers of human NASH patients.


  Methods Top


The analyses presented in this article were conducted on datasets obtained from the National Institutes of Health (NIH)'s National Center for Biotechnology Information Gene Expression Omnibus (GEO) Database (www.ncbi.nlm.nih.gov/geo/). Each dataset obtained and analyzed from this database consisted of mRNA microarray data taken from liver biopsies from individual human patients. Within each dataset, patient groups were separated based on their clinical liver diagnosis. We performed multiple comparisons tests to analyze variations in the expression levels of IRE1 (ERN1). [Table 1] lists the analyses that were performed to understand the associations of variations in the expression of IRE1 gene with NASH.
Table 1: Comparing gene expression in non-nonalcoholic steatohepatitis versus nonalcoholic steatohepatitis human patient livers

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All statistical tests were performed in R software (R Core Team (2017). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria). Wilcoxon signed-rank tests were performed to test for significant variations in gene expression levels between the two patient groups involved in this study (non-NASH and NASH). In all comparison tests, P < 0.05 was considered to be statistically significant.


  Results Top


We examined the expression levels of the primary UPR transducer IRE1 in the livers of human NASH patients and non-NASH individuals based on the microRNA datasets of public domain. The mRNA microarray data showing total gene expression were obtained from the GSE83452 dataset from the GEO database. Specifically, human liver biopsy samples were obtained from a total of 152 obese patients, 148 of whom were diagnosed as either non-NASH (n = 44) or NASH (n = 104)[8] [Table 1].

Wilcoxon signed-rank tests were performed to compare gene expression levels in patients diagnosed with NASH with those without NASH, by testing the null hypothesis that gene expression levels in the obese patients without NASH and the obese patients with NASH are equal. As shown in [Figure 1], there was very strong evidence that IRE1 mRNA expression levels are significantly decreased in the NASH livers in comparison to non-NASH livers (P < 0.001).
Figure 1: Expression levels of IRE1 mRNA in livers of the obese patients with NASH and the obese patients without NASH. The mean relative intensity for each gene is shown. Error bars show positive and negative standard errors. Statistically significant differences in the NASH group from the non-NASH group are indicated by **(P < 0.001). NASH: Nonalcoholic steatohepatitis

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  Discussion Top


The involvement of UPR in the pathogenesis of NAFLD has been intensively investigated. However, in the past 20 years, a number of conflicting studies in regard to activation of the UPR in the livers of NAFLD or NASH patients or animal models have been published. Indeed, many reported that the UPR signaling was activated to act as a driving force in the progression of NASH. In contrast, an increasing number of studies showed that UPR, particularly the IRE1-mediated UPR, was repressed in the livers of NASH patients or animal models.[9],[10],[11] In this study, based on the gene expression profiles in the livers of human NASH patients, we demonstrated that the expression levels of IRE1 were indeed decreased in the livers of human obese patients with NASH, compared to those of obese patients without NASH [Figure 1]. Although the expression levels of IRE1 may not be necessarily consistent with IRE1 RNase activity, our analysis result is consistent with the role of IRE1-mediated UPR in preserving cellular homeostasis and functions and in protecting organisms from injuries caused by stressors. However, we should note that the simple comparison performed in this study did not include additional factors; for example, the age factor. It is possible that UPR may be activated in a particular stage of NASH where the pathological condition causes ER stress and UPR activation in the liver. This question warrants further investigation of UPR involvement in NASH with the analysis of additional human NASH gene expression datasets.

Acknowledgment

El Hussain Shamsa is an undergraduate student at the University of Michigan, who participated in the Summer Undergraduate Research Program in Dr. Zhang's laboratory at the Center for Molecular Medicine and Genetics of Wayne State University School of Medicine.

Financial support and sponsorship

Portions of this work was supported by NIH grants DK090313 and ES017829 (to KZ), AR066634 (to DF and KZ), and American Heart Association Grants 0635423Z and 09GRNT2280479 (to KZ).

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: Coordination of gene transcriptional and translational controls. Genes Dev 1999;13:1211-33.  Back to cited text no. 1
    
2.
Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007;8:519-29.  Back to cited text no. 2
    
3.
Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature 2008;454:455-62.  Back to cited text no. 3
    
4.
Zhang K. Integration of ER stress, oxidative stress and the inflammatory response in health and disease. Int J Clin Exp Med 2010;3:33-40.  Back to cited text no. 4
    
5.
Zhang K, Kaufman RJ. Signaling the unfolded protein response from the endoplasmic reticulum. J Biol Chem 2004;279:25935-8.  Back to cited text no. 5
    
6.
Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221-31.  Back to cited text no. 6
    
7.
Brunt EM. Nonalcoholic steatohepatitis: Definition and pathology. Semin Liver Dis 2001;21:3-16.  Back to cited text no. 7
    
8.
Lefebvre P, Lalloyer F, Baugé E, Pawlak M, Gheeraert C, Dehondt H, et al. Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin. JCI Insight 2017;2. pii: 92264.  Back to cited text no. 8
    
9.
Wang JM, Qiu Y, Yang Z, Kim H, Qian Q, Sun Q, et al. IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs. Sci Signal 2018;11. pii: eaao4617.  Back to cited text no. 9
    
10.
Yang L, Calay ES, Fan J, Arduini A, Kunz RC, Gygi SP, et al. METABOLISM. S-nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science 2015;349:500-6.  Back to cited text no. 10
    
11.
Puri P, Mirshahi F, Cheung O, Natarajan R, Maher JW, Kellum JM, et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 2008;134:568-76.  Back to cited text no. 11
    


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