The Unfolded Protein Response Sensor IRE1 Regulates Collagen Secretion and Liver Fibrosis

Core Concepts

The unfolded protein response sensor IRE1 controls collagen production and secretion in the liver, thereby regulating the development of liver fibrosis and other chronic liver diseases.

Abstract

The content explores the role of the unfolded protein response (UPR) sensor IRE1 in the regulation of collagen production and secretion, and its implications for liver disease. Key highlights:

Genetic ablation of the IRE1 sensor reduces liver damage and collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl4) administration or high-fat diet (HFD).

Proteomic and transcriptomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1) as a major IRE1-induced gene. P4HB is critical for collagen maturation.

Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the endoplasmic reticulum (ER) and altered secretion, a phenotype rescued by P4HB overexpression.

Analysis of human NASH samples showed a positive correlation between IRE1/XBP1 signaling and P4HB expression levels, as well as with disease severity.

The results collectively establish a role of the IRE1/P4HB axis in the regulation of collagen production and its significance in the pathogenesis of various liver disease states.

Stats

The content includes the following key data:

Reduced liver damage and collagen deposition in IRE1-deficient mice upon CCl4 or HFD treatment
Downregulation of P4HB, a key collagen maturation factor, in IRE1-deficient livers
Increased intracellular collagen aggregation and reduced secretion in IRE1-deficient cells
Rescue of collagen secretion defects in IRE1-deficient cells by overexpression of P4HB
Positive correlation between IRE1/XBP1 signaling and P4HB expression in human NASH samples
Positive correlation between IRE1/XBP1 signaling and markers of liver disease severity in human NASH samples

Quotes

"Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl4) administration or by high fat diet."
"Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER and altered secretion, a phenotype rescued by P4HB overexpression."
"Taken together, our results collectively establish a role of the IRE1/P4HB axis in the regulation of collagen production and its significance in the pathogenesis of various disease states."

Key Insights Distilled From

The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis

by Hazari,Y., U... at www.biorxiv.org 05-02-2023

https://www.biorxiv.org/content/10.1101/2023.05.02.538835v1

Deeper Inquiries

What other signaling pathways or cellular processes might be involved in regulating collagen production and secretion beyond the IRE1/P4HB axis

In addition to the IRE1/P4HB axis, several other signaling pathways and cellular processes play crucial roles in regulating collagen production and secretion. One key pathway is the TGF-β signaling pathway, which is a major inducer of collagen synthesis and fibrosis in various tissues, including the liver. TGF-β activates downstream effectors such as Smad proteins, leading to the transcriptional upregulation of collagen genes. Additionally, the MAPK/ERK pathway can also modulate collagen production by regulating the activity of transcription factors involved in collagen gene expression. Furthermore, the PI3K/Akt pathway has been implicated in collagen synthesis through its effects on protein translation and stability. Cellular processes such as autophagy and proteasomal degradation also play critical roles in maintaining collagen homeostasis by clearing misfolded or excess collagen proteins. Overall, a network of signaling pathways and cellular mechanisms collaborates to tightly regulate collagen production and secretion in health and disease.

How might the findings from this study be leveraged to develop novel therapeutic strategies for liver fibrosis and other chronic liver diseases

The findings from this study offer valuable insights that can be leveraged to develop novel therapeutic strategies for liver fibrosis and other chronic liver diseases. Targeting the IRE1/P4HB axis could be a promising approach to modulate collagen production and secretion, thereby reducing fibrosis progression. Potential therapeutic interventions could involve small molecule inhibitors targeting IRE1 or P4HB to disrupt collagen synthesis and deposition. Additionally, strategies aimed at enhancing the activity of P4HB or promoting proper collagen folding could help alleviate fibrosis and improve liver function. Furthermore, combination therapies targeting multiple pathways involved in collagen regulation, such as TGF-β signaling or autophagy, could provide synergistic effects in mitigating fibrosis progression. Overall, the identification of the IRE1/P4HB axis as a key regulator of collagen homeostasis opens up new avenues for the development of targeted therapies for liver fibrosis and related conditions.

Given the central role of collagen in various connective tissue disorders, could the IRE1/P4HB axis be a common regulatory mechanism in the pathogenesis of diseases beyond the liver

Given the central role of collagen in various connective tissue disorders, including fibrosis, arthritis, and cardiovascular diseases, the IRE1/P4HB axis could indeed represent a common regulatory mechanism in the pathogenesis of diseases beyond the liver. Dysregulation of collagen production and secretion is a hallmark of many pathological conditions involving fibrosis and tissue remodeling. The IRE1/P4HB axis, by controlling collagen maturation and secretion, could have broad implications in the pathophysiology of these diseases. Targeting this axis may offer a universal approach to modulate collagen homeostasis and mitigate fibrotic processes in different tissues. Further research into the role of IRE1 and P4HB in various connective tissue disorders could unveil their therapeutic potential as targets for intervention in a wide range of diseases characterized by collagen dysregulation.