A Fibrosis‐Independent Hepatic Transcriptomic Signature Identifies Drivers of Disease Progression in Primary Sclerosing Cholangitis

Gindin, Yevgeniy; Chung, Chuhan; Jiang, Zhaoshi; Zhou, Jing Zhu; Xu, Jun; Billin, Andrew N.; Myers, Robert P.; Goodman, Zachary; Landi, Abdolabdolamir; Houghton, Michael; Green, Richard M.; Levy, Cynthia; Kowdley, Kris V.; Bowlus, Christopher L.; Muir, Andrew J.; Trauner, Michael

doi:10.1002/hep.31488

Cited by 17 publications

(14 citation statements)

References 29 publications

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“…The UPR decreases ER stress and restores cellular homeostasis, and dysregulation of the UPR has been associated with several liver diseases. Notably, adult patients with the cholestatic liver disease PSC who have downregulation of ATF6 expression are at increased risk for more rapid disease progression and clinical complications 22 . Additionally, the IRE1α/XBP1 pathway has been studied in adult liver disease progression as well as murine models of ER stress.…”

Section: Discussionmentioning

confidence: 99%

IRE1α/XBP1 pathway expression is impaired in pediatric cholestatic liver disease explants

Kriegermeier

Hyon

LeCuyer

et al. 2022

Preprint

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Background and Aims: Cholestatic liver diseases (CLD) are the leading indication for pediatric liver transplantation. Bile acids are known to trigger endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is a coordinated response which functions to decrease ER stress and maintain cellular homeostasis. Dysregulation of the UPR, specifically the inositol-requiring enzyme 1α/X-box protein 1 (IRE1α/XBP1) pathway, has been associated with several adult liver diseases. In this study, we sought to evaluate the UPR in pediatric livers with end-stage CLD and hypothesized there would be altered IRE1α/XBP1 pathway activation compared to normal control livers. Methods: We evaluated 34 human liver ex-plants which included pediatric CLD, pediatric normal, pediatric non-cholestatic liver disease (autoimmune hepatitis, AIH), adult CLD and adult normal cohorts. We performed RNA sequencing (RNAseq), qPCR and western blotting to identify significantly different pathway activation and assess for changes within the UPR. Results: Pathway analysis of RNAseq data demonstrated that protein processing in the ER was a significantly differentially expressed pathway in all liver disease cohorts compared to appropriate controls. Pediatric CLD samples had evidence of ongoing ER stress with activation of the PKR-like ER kinase (PERK) pathway but had significantly decreased expression of the IRE1α/XBP1 pathway of the UPR compared to normal controls. Pediatric AIH samples had similar activation of the PERK pathway but notably did not have decreased activation of the IRE1α/XBP1 pathway compared to normal controls.

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Section: Discussionmentioning

confidence: 99%

IRE1α/XBP1 pathway expression is impaired in pediatric cholestatic liver disease explants

Kriegermeier

Hyon

LeCuyer

et al. 2022

Preprint

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“…This suggests that the enhanced hepatic XBP1 pathway is protective in FXR deficient mice, which is consistent with the known adaptive and protective role of XBP1 in reducing or resolving ER stress. A recent transcriptome study using liver biopsies from PSC patients demonstrated that the expression of UPR genes was lower in the group of patients who were at increased risk for adverse PSC-related clinical events (15). Furthermore, we have shown in murine models that weanling mice are unable to adequately activate the hepatic XBP1 and other UPR pathways in response to bile acid or pharmacologically-induced ER stress, and this inadequate hepatic XBP1 activation causes increased liver injury and apoptosis (30).…”

Section: Discussionmentioning

confidence: 99%

Hepatic Deletion of X-box Binding Protein 1 in Farnesoid X Receptor Null Mice Leads to Enhanced Liver Injury

Khalafalla

Chung

et al. 2022

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Background & AimsFarnesoid X receptor (FXR) regulates bile acid metabolism and FXR null (Fxr-/-) mice have elevated bile acid levels and progressive liver injury. The inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP1) pathway is a protective pathway of the unfolded protein response (UPR) that is activated in response to ER stress. In this study we sought to determine the role of the UPR in Fxr-/- mice.Approach & ResultsWe examined hepatic UPR gene and protein expression in 10- and 24-week-old wild type (WT) and Fxr-/- mice. Hepatic XBP1 and other UPR pathways were activated in 24-week-old Fxr-/- mice, but not WT mice. To further determine the role of the liver UPR activation in Fxr-/- mice, we generated mice with FXR and liver-specific XBP1 double knockout (DKO, Fxr-/-Xbp1LKO) and Fxr-/-Xbp1fl/fl single knockout (SKO) mice and characterized their phenotypes at different ages. DKO mice demonstrated enhanced liver injury, apoptosis and fibrosis compared with SKO mice. RNA-seq revealed increased gene expression in apoptosis, inflammation and cell proliferation pathways in DKO mice. The proapoptotic C/EBP-homologous protein (CHOP) pathway was activated in DKO mice. At age 60 weeks, all DKO mice and no SKO mice spontaneously developed liver tumors.ConclusionsThe hepatic XBP1 pathway is activated in older Fxr-/- mice and has a protective role. The potential interaction between XBP1 and FXR signaling may be important in modulating the hepatocellular cholestatic stress responses.

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“…Pathway analysis demonstrated increased expression of the liver UPR pathways in the NR:HBR group compared to the NR:Mild group. It has been previously reported that selected UPR genes are down-regulated in PSC patients with a high risk of developing PSC-related complications (7). Patients with progressive NASH also have UPR dysregulation and an attenuated UPR response compared to patients with benign hepatic steatosis (24), although this was not seen in other patient populations (25).…”

Section: Discussionmentioning

confidence: 99%

“…The hepatic UPR is important in the pathogenesis of many liver diseases including viral hepatitis, non-alcoholic fatty liver disease, alpha-1 antitrypsin deficiency, alcoholic liver disease and ischemia-reperfusion injury (9-11). Finally, in a recent study of PSC patients, differential expression of UPR genes was identified in patients who were at high risk for liver-related complications (7). Unfortunately, the role of the UPR in human cholestasis and cholestatic liver injury remains poorly understood.…”

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confidence: 99%

“…A major reason for the lack of effective medical therapies for cholestatic liver disorders is our incomplete understanding of the disease pathogenesis and progression. Recent human and animal studies indicate that the liver unfolded protein response (UPR) is important in the pathogenesis of cholestatic liver injury and may be prognostic for liver-related complications in patients with PSC (7-9).…”

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confidence: 99%

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Expression of Unfolded Protein Response Genes in Post-transplantation Liver Biopsies

Taylor

Celaj

et al. 2022

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Cholestatic liver diseases are a major source of morbidity and mortality that can progress to end-stage liver disease. There are few effective medical therapies for primary biliary cholangitis, primary sclerosing cholangitis and other cholestatic liver diseases, in part, due to our incomplete understanding of the pathogenesis of cholestatic liver injury. The hepatic unfolded protein response (UPR) is an adaptive cellular response to endoplasmic reticulum stress that is important in the pathogenesis of many liver diseases and recent animal studies have demonstrated the importance of the UPR in the pathogenesis of cholestatic liver injury. However, the role of the UPR in human cholestatic liver diseases is largely unknown. In this study, we utilized liver biopsies from patients after liver transplantation as a disease model to determine the transcriptional profile and hepatic UPR gene expression that is associated with liver injury and cholestasis. RNA-seq analysis revealed that patients with hyperbilirubinemia had enhanced expression of hepatic UPR pathways. Alternatively, liver biopsy samples from patients with acute rejection had enhanced gene expression of LAG3 and CDK1. Pearson correlation analysis of serum alanine aminotransferase, aspartate aminotransferase and total bilirubin levels demonstrated significant correlations with the hepatic expression of several UPR genes, as well as genes involved in hepatic bile acid metabolism and inflammation. In contrast, serum alkaline phosphatase levels were correlated with the level of hepatic bile acid metabolism gene expression but not liver UPR gene expression.ConclusionOverall, these data indicate that hepatic UPR pathways are increased in cholestatic human liver biopsy samples and supports an important role of the UPR in the mechanism of human cholestatic liver injury.

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A Fibrosis‐Independent Hepatic Transcriptomic Signature Identifies Drivers of Disease Progression in Primary Sclerosing Cholangitis

Cited by 17 publications

References 29 publications

IRE1α/XBP1 pathway expression is impaired in pediatric cholestatic liver disease explants

IRE1α/XBP1 pathway expression is impaired in pediatric cholestatic liver disease explants

Hepatic Deletion of X-box Binding Protein 1 in Farnesoid X Receptor Null Mice Leads to Enhanced Liver Injury

Expression of Unfolded Protein Response Genes in Post-transplantation Liver Biopsies

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