Endoplasmic reticulum stress in liver diseases

Ajoolabady, Amir; Kaplowitz, Neil; Lebeaupin, Cynthia; Kroemer, Guido; Kaufman, Randal J.; Malhi, Harmeet; Ren, Jun

doi:10.1002/hep.32562

Cited by 142 publications

(87 citation statements)

References 131 publications

(232 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pediatric cholestatic liver diseases are the leading indication for pediatric liver transplantation and there are currently no effective medical therapies that reduce the need for liver transplantation. During cholestasis, high intrahepatic concentrations of bile acids increase ER stress and hepatocellular injury, and an effective UPR response is essential to restore cellular homeostasis 2–5 Inadequate activation or dysregulation of the IREα/XBP1 pathway of the UPR has been implicated in the pathogenesis of several liver diseases 23 . Puri et al demonstrated that decreased levels of XBP1s protein expression was associated with the development of steatohepatitis in adult patients, although, although there remains some conflicting data 8, 24, 25 .…”

Section: Discussionmentioning

confidence: 99%

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

Kriegermeier

Hyon

LeCuyer

et al. 2022

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Kriegermeier

Hyon

LeCuyer

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Recently, our group utilized a bile acid feeding model of cholestasis and bile acid toxicity to demonstrate that, compared to adult mice, young mice had decreased XBP1s downstream target activation, with a resultant enhanced susceptibility to bile acid induced liver injury and apoptosis [ 15 ]. Additionally, inadequate activation of the IREα/XBP1 pathway has been implicated in the pathogenesis of several adult liver diseases [ 24 ]. Puri et al demonstrated that decreased levels of XBP1s protein expression were associated with the development of steatohepatitis in adult patients, although there remains some conflicting data on UPR expression in other NAFLD/NASH studies [ 8 , 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

Inositol-requiring enzyme 1α/X-box protein 1 pathway expression is impaired in pediatric cholestatic liver disease explants

et al. 2022

View full text Add to dashboard Cite

Background Increased intrahepatic bile acids cause endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) is activated to maintain homeostasis. UPR dysregulation, including the inositol-requiring enzyme 1α/X-box protein 1 (IRE1α/XBP1) pathway, is associated with adult liver diseases but has not been characterized in pediatric liver diseases. We evaluated hepatic UPR expression in pediatric cholestatic liver disease (CLD) explants and hypothesize that an inability to appropriately activate the hepatic IRE1α/XBP1 pathway is associated with the pathogenesis of CLD. Methods We evaluated 34 human liver explants, including: pediatric CLD (Alagille, ALGS, and progressive familial intrahepatic cholestasis, PFIC), pediatric non-cholestatic liver disease controls (autoimmune hepatitis, AIH), adult CLD, and normal controls. We performed RNA-seq, quantitative PCR, and western blotting to measure expression differences of the hepatic UPR and other signaling pathways. Results Pathway analysis demonstrated that the KEGG ‘protein processing in ER’ pathway was downregulated in pediatric CLD compared to normal controls. Pediatric CLD had decreased hepatic IRE1α/XBP1 pathway gene expression and decreased protein expression of phosphorylated IRE1α compared to normal controls. IRE1α/XBP1 pathway gene expression was also decreased in pediatric CLD compared to AIH disease controls. Conclusions Pediatric CLD explants have decreased expression of the protective IRE1α/XBP1 pathway and down-regulated KEGG protein processing in the ER pathways. IRE1α/XBP1 pathway expression differences occur when compared to both normal and non-cholestatic disease controls. Attenuated expression of the IRE1α/XBP1 pathway is associated with cholestatic diseases and may be a target for future therapeutics.

show abstract

“…It is now abundantly clear that ER stress is associated with fatty liver disease in humans and mouse models thereof (3). It is also likely that ER stress contributes to disease pathogenesis, since mice with an impaired ability to respond to ER stress in the liver are sensitized to experimental insults that lead to liver injury including alcohol, western diets, and pharmacotoxins that target the liver (4). The pathways by which ER stress affects hepatic function and exacerbates liver injury are still being characterized.…”

Section: Introductionmentioning

confidence: 99%

Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes

Shah

Huck

Duncan

et al. 2023

Preprint

View full text Add to dashboard Cite

In all eukaryotic cell types, the unfolded protein response (UPR) upregulates factors that promote protein folding and misfolded protein clearance to help alleviate endoplasmic reticulum (ER) stress. Yet ER stress in the liver is uniquely accompanied by the suppression of metabolic genes, the coordination and purpose of which is largely unknown. Here, we used unsupervised machine learning to identify a cluster of correlated genes that were profoundly suppressed by persistent ER stress in the liver. These genes, which encode diverse functions including metabolism, coagulation, drug detoxification, and bile synthesis, are likely targets of the master regulator of hepatocyte differentiation HNF4α. The response of these genes to ER stress was phenocopied by liver-specific deletion of HNF4α. Strikingly, while deletion of HNF4α exacerbated liver injury in response to an ER stress challenge, it also diminished UPR activation and partially preserved ER ultrastructure, suggesting attenuated ER stress. Conversely, pharmacological maintenance of hepatocyte identity in vitro enhanced sensitivity to stress. Several pathways potentially link HNF4α to ER stress sensitivity, including control of expression of the tunicamycin transporter MFSD2A; modulation of IRE1/XBP1 signaling; and regulation of Pyruvate Dehydrogenase. Together, these findings suggest that HNF4α activity is linked to hepatic ER homeostasis through multiple mechanisms.

show abstract

Endoplasmic reticulum stress in liver diseases

Cited by 142 publications

References 131 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

Inositol-requiring enzyme 1α/X-box protein 1 pathway expression is impaired in pediatric cholestatic liver disease explants

Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes

Contact Info

Product

Resources

About