Journal Article

Persistent Lipid Accumulation Leads to Persistent Exacerbation of Endoplasmic Reticulum Stress and Inflammation in Progressive NASH via the IRE1α/TRAF2 Complex

Li, Xiuyan, Ji, Shaoxiu, Zhu, Xiuying, Song, Hongfei, Meng, Xiangbo, Liu, Jibin, Feng, Quansheng, Lei, Na, Mu, Jie, Zeng, Ling

2023

Overview

Non-alcoholic steatohepatitis (NASH) is a metabolic disorder that often leads to other severe liver diseases, yet treatment options are limited. Endoplasmic reticulum (ER) stress is an important pathogenetic mechanism of NASH and plays a key role in tandem steatosis as well as liver inflammation. This study aims to develop a progressive NASH model through sustained lipid accumulation and to elucidate its molecular mechanism through IRE1α/TRAF2 complex. Male SD rats were fed a high-fat diet (HFD) for 4, 8, and 12 weeks to induce progressive NASH. MRNA sequencing and PPI analysis were used to screen core genes. Transmission electron microscopy, immunofluorescence staining, ELISA, qRT-PCR, and Western blotting were used at each time point to compare differences between each index of progressive NASH at 4, 8, and 12 weeks. Sustained lipid accumulation led to structural disruption of the ER, a reduction in ER number, and an increase of lipid droplet aggregation in hepatocytes. Persistent lipid accumulation led to a persistent increase in mRNA and protein expression of the IRE1α/TRAF2 complex, IKK/IκB/NF-κB signaling pathway and ASK1/JNK1 signaling pathway, and TNF-α, IL-1β, and IL-6 also continued to increase. Persistent lipid accumulation led to a persistent exacerbation of ER stress and inflammation in progressive NASH via the IRE1α/TRAF2 complex.

• Publisher: MDPI AG,MDPI
• Subject: Animals / ASK1/JNK1 signaling pathway / Biosynthesis / Body fat / Collagen / Endoplasmic reticulum / Endoplasmic Reticulum Stress / Endoribonucleases - genetics / Endoribonucleases - metabolism / Fatty liver / Genes / Health aspects / High density lipoprotein / IKK/IκB/NF-κB signaling pathway / Inflammation / Inflammation - metabolism / IRE1α/TRAF2 complex / Kinases / lipid accumulation / Lipids / Liver - metabolism / Liver cancer / Liver diseases / Male / Membrane proteins / Metabolism / Non-alcoholic Fatty Liver Disease - metabolism / non-alcoholic steatohepatitis / Oxidative stress / Physiological aspects / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Proteins / Rats / Rats, Sprague-Dawley / Sterols / TNF Receptor-Associated Factor 2 - genetics / TNF Receptor-Associated Factor 2 - metabolism