Loading…
Cholesterol accumulation in hepatocytes mediates IRE1/p38 branch of endoplasmic reticulum stress to promote nonalcoholic steatohepatitis
Non-alcoholic fatty liver disease (NAFLD), based on the elevating obesity incidence, is one of the major health issue worldwide. Transition from NAFLD to non-alcoholic steatohepatitis (NASH) is driven by increased apoptosis and is relevant to higher morbidity rates. In regard to limited understandin...
Saved in:
Published in: | Free radical biology & medicine 2022-10, Vol.191, p.1-7 |
---|---|
Main Authors: | , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | Non-alcoholic fatty liver disease (NAFLD), based on the elevating obesity incidence, is one of the major health issue worldwide. Transition from NAFLD to non-alcoholic steatohepatitis (NASH) is driven by increased apoptosis and is relevant to higher morbidity rates. In regard to limited understanding on cholesterol mediated hepatocyte alterations in NALFD/NASH transition, we investigated endoplasmic reticulum (ER) stress and related apoptosis. Our findings suggest that cholesterol upregulates ER stress and enhances C/EBP homologous protein (CHOP) either in hypercholesterolemic rabbits or in hepatocytes treated with liposome-cholesterol complex. Mechanistically, cholesterol accumulation in hepatocytes activates IRE1/p38 branch of ER stress, stimulating CHOP levels. In liver tissues of cholesterol fed rabbits, α-tocopherol supplementation decreased IRE1/p38/CHOP activation and prevented NASH development. Thus, our study provides a critical role of hepatocyte cholesterol in inducing IRE1/p38/CHOP pathway and suggests novel candidates for therapeutic targets against NASH.
[Display omitted]
•Hepatocyte cholesterol accumulation leads to endoplasmic reticulum stress.•IRE1-p38-CHOP signaling of endoplasmic reticulum stress is related with apoptosis.•Endoplasmic reticulum stress and p38 inhibition mitigates CHOP activation.•α-Tocopherol prevents cholesterol induced nonalcoholic steatohepatitis. |
---|---|
ISSN: | 0891-5849 1873-4596 |
DOI: | 10.1016/j.freeradbiomed.2022.08.024 |