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| Status |
Public on Jun 23, 2022 |
| Title |
The IRE1α/XBP1 pathway expression is impaired in pediatric cholestatic liver disease explants |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Background/Aims: Cholestatic liver diseases (CLD) are the leading indication for pediatric liver transplantation. Increased intrahepatic bile acid concentrations 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 several adult liver diseases. We evaluated hepatic UPR expression in pediatric patients with end-stage CLD 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. Cohorts included: 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: Metascape 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 p-IRE1α compared to normal controls. These CLD changes were not disease-specific to ALGS or PFIC. IRE1α/XBP1 pathway gene expression was decreased in pediatric CLD compared to AIH disease controls. Conclusion: Pediatric CLD explants have decreased gene and protein 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 could be targeted to treat pediatric CLD.
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| Overall design |
Samples are human explanted livers: 9 pediatric (<18 years of age) normal livers, 10 pediatric cholestatic liver disease (CLD) livers (5 with Alagille syndrome, 5 with progressive familial intrahepatic cholestasis), 5 pediatric autoimmune hepatitis livers, 3 adult cholestatic liver disease livers (1 with primary sclerosing cholangitis and 2 with primary biliary cholangitis), and 7 adult (>18 years of age) normal livers
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| Contributor(s) |
Kriegermeier A, Hyon A, LeCuyer B, Hubchak S, Liu X, Green RM |
| Citation(s) |
36520816 |
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| Submission date |
Jun 17, 2022 |
| Last update date |
Jan 06, 2023 |
| Contact name |
Alyssa Kriegermeier |
| E-mail(s) |
akriegermeier@luriechildrens.org
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| Phone |
8474146125
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| Organization name |
Ann and Robert H. Lurie Children's Hospital of Chicago
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| Department |
GI/Hepatology/Nutrition
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| Street address |
225 E. Chicago
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| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60611 |
| Country |
USA |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (34)
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| GSM6252622 |
liver, adult normal, 4 |
| GSM6252623 |
liver, adult normal, 5 |
| GSM6252624 |
liver, adult normal, 6 |
| GSM6252625 |
liver, adult normal, 7 |
| GSM6252626 |
liver, pediatric normal, 1 |
| GSM6252627 |
liver, pediatric normal, 2 |
| GSM6252628 |
liver, pediatric normal, 3 |
| GSM6252629 |
liver, pediatric normal, 4 |
| GSM6252630 |
liver, pediatric normal, 5 |
| GSM6252631 |
liver, pediatric normal, 6 |
| GSM6252632 |
liver, pediatric normal, 7 |
| GSM6252633 |
liver, pediatric normal, 8 |
| GSM6252634 |
liver, pediatric normal, 9 |
| GSM6252635 |
liver, adult cholestatic liver disease, PSC |
| GSM6252636 |
liver, adult cholestatic liver disease, PBC 1 |
| GSM6252637 |
liver, adult cholestatic liver disease, PBC 2 |
| GSM6252638 |
liver, pediatric cholestatic liver disease, PFIC, case 1 |
| GSM6252639 |
liver, pediatric cholestatic liver disease, PFIC, case 2 |
| GSM6252640 |
liver, pediatric cholestatic liver disease, PFIC, case 3 |
| GSM6252641 |
liver, pediatric cholestatic liver disease, PFIC, case 4 |
| GSM6252642 |
liver, pediatric cholestatic liver disease, PFIC, case 5 |
| GSM6252643 |
liver pediatric choelstatic liver disease, ALGS case 1 |
| GSM6252644 |
liver pediatric choelstatic liver disease, ALGS case 2 |
| GSM6252645 |
liver pediatric choelstatic liver disease, ALGS case 3 |
| GSM6252646 |
liver pediatric choelstatic liver disease, ALGS case 4 |
| GSM6252647 |
liver pediatric choelstatic liver disease, ALGS case 5 |
| GSM6252648 |
liver, pediatric autoimmune hepatitis, case 1 |
| GSM6252649 |
liver, pediatric autoimmune hepatitis, case 2 |
| GSM6252650 |
liver, pediatric autoimmune hepatitis, case 3 |
| GSM6252651 |
liver, pediatric autoimmune hepatitis, case 4 |
| GSM6252652 |
liver, pediatric autoimmune hepatitis, case 5 |
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| Relations |
| BioProject |
PRJNA850385 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE206364_RAW.tar |
6.6 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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