Chronic inflammatory liver disease – cell stress mechanisms identified by RNA-Seq as prognostic factor

Primary sclerosing cholangitis (PSC) is a rare, chronic, inflammatory disease of the bile ducts and is difficult to treat, since its causes have not yet been adequately researched. Using RNA sequencing, an international research consortium led by Michael Trauner, Head of MedUni Vienna’s Division of Gastroenterology and Hepatology (Department of Medicine III), has now succeeded in identifying a new prognostic factor for PSC from liver biopsies. This is so-called cellular ER stress. ER stress is the name given to a complex cellular response to stress caused by the build-up of misfolded proteins in the endoplasmic reticulum (ER).

PSC is a rare disease with a poor prognosis and can lead to cirrhosis of the liver or bile duct cancer. It affects 0.01% of the population but, even though it is rare, PSC is responsible for more than 10% of all liver transplants, making it the third most common indication on liver transplant waiting lists in Europe. In the recent study, which has now been published in the leading journal Hepatology, the researchers were able to identify a molecular signature for ER stress both in the liver cells (hepatocytes) and also in the bile duct epithelium — and notably as a stand-alone factor that is independent of the disease stage or degree of liver fibrosis (laying down of scar tissue) as a precursor to possible liver cirrhosis.

“Using transcriptional analysis, we were able to identify a personalised molecular signature of primary sclerosing cholangitis, which shows that patients with an impaired response to ER stress have a poorer prognosis with a higher incidence of complications,” explains Trauner. “This discovery also opens up new treatment options, since ER stress can be counteracted with drugs.”

UPR pathway highlighting gene‐expression differences
between the low‐risk and high‐risk PSC clusters

The nodes in the pathway are shaded proportional to the P value of differential gene expression between low‐risk and high‐risk PSC clusters. Genes with smaller P values are darker. Differentially expressed genes associated with this pathway are provided in the table as an inset. The pathway diagram was generated using Ingenuity Pathway Analysis. Abbreviations: ASK1, mitogen‐activated protein kinase kinase kinase 5; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; BCL2, BCL2 apoptosis regulator; BIP, heat shock protein family A (Hsp70) member 5; c/EBP, CCAAT Enhancer Binding Protein Beta; CALR, calreticulin; CANX, calnexin; CHOP, DNA damage inducible transcript 3; EDEM, ER degradation enhancing alpha‐mannosidase like protein 1; EIF2α, eukaryotic translation initiation factor 2A; ERO1‐Lβ, endoplasmic reticulum oxidoreductase 1 beta; GADD34, protein phosphatase 1 regulatory subunit 15A; GRP94, heat shock protein 90 beta family member 1; INSIG1, insulin induced gene 1; IRE1, endoplasmic reticulum to nucleus signaling 1; JNK1, mitogen‐activated protein kinase 8; MBTPS, membrane bound transcription factor peptidase; MKK7, mitogen‐activated protein kinase kinase 7; NRF2, “nuclear factor, erythroid 2 like 2”; P58IPK, DnaJ heat shock protein family (Hsp40) member C3; PDI, protein disulfide isomerase; PERK, eukaryotic translation initiation factor 2 alpha kinase 3; PPARγ, peroxisome proliferator activated receptor gamma; SCAP, SREBF chaperone; SREBP, sterol regulatory element binding transcription factor; TRAF2, TNF receptor associated factor 2; XBP1, X‐box binding protein 1.

Since the build-up of potentially toxic bile acids in cholestasis results in ER stress, it is now being attempted to restore this balance pharmacologically using the new bile acid therapeutics that are available. Beneficial effects can reportedly be expected from drugs already in clinically testing — however, more research has already been initiated to explore this further.

Source – Medical University of Vienna