MiR-149 attenuates endoplasmic reticulum stress-induced inflammation and apoptosis in nonalcoholic fatty liver disease by negatively targeting ATF6 pathway

Zhiyuan Chen; Yaling Liu; Li Yang; Peng Liu; Yu Zhang; Xiangyang Wang

doi:10.1016/j.imlet.2020.03.003

MiR-149 attenuates endoplasmic reticulum stress-induced inflammation and apoptosis in nonalcoholic fatty liver disease by negatively targeting ATF6 pathway

Immunol Lett. 2020 Jun:222:40-48. doi: 10.1016/j.imlet.2020.03.003. Epub 2020 Mar 16.

Authors

Zhiyuan Chen¹, Yaling Liu², Li Yang², Peng Liu², Yu Zhang², Xiangyang Wang³

Affiliations

¹ Department of Gastroenterology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, 410005, PR China. Electronic address: chenzhiyuan@hunnu.edu.cn.
² Department of Gastroenterology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, 410005, PR China.
³ Department of Gastroenterology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, 410005, PR China. Electronic address: wangxiangyang@csu.edu.cn.

PMID: 32194141
DOI: 10.1016/j.imlet.2020.03.003

Abstract

This study aimed to research the effect of miR-149 on endoplasmic reticulum stress (ERS)-induced inflammation and apoptosis in non-alcoholic fatty liver disease (NAFLD). The mouse model with NAFLD was established by feeding with a high-fat diet, and the model establishment was subsequently confirmed by H&E staining and oil red O staining. MiR-149 agomir was injected into NAFLD mice to observe changes in liver tissues. After cell transfection, qRT-PCR and Western blot were performed to measure the expressions of lipid metabolism-related proteins (SCD-1, PPARα, and ABCA1), miR-149 and ATF6. Luciferase reporter gene assay was applied to verify the relationship between miR-149 and ATF6. Inflammatory factors (TNF-α, IL-1β, IL-6 and NF-κB) and apoptotic-related factors (caspase-12 and CHOP) were measured by ELISA and flow cytometry. qRT-PCR and Western blot were applied to detect expressions of ATF6 signaling pathway-related proteins (GRP94 and Akt). NAFLD progression was attenuated in mice injected with miR-149 agomir. The expression of miR-149 was reduced in liver tissues of NAFLD mice, while the expression of ATF6 was increased. Transfection of miR-149 can result in a decrease of ATF6 expression. ATF6 was a target gene of miR-149. MiR-149 could down-regulate the expressions of inflammatory factors and apoptotic-related factors. MiR-149 could down-regulate expressions of ATF6 signaling pathway-related proteins. MiR-149 alleviates ERS-induced inflammation and apoptosis by down-regulating the ATF6 signaling pathway, thus inhibiting the progression of NAFLD.

Keywords: ATF6; ATF6 signaling pathway; Apoptosis; Endoplasmic reticulum stress; Inflammation; MiR-149; NAFLD.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 6 / genetics
Activating Transcription Factor 6 / metabolism*
Animals
Apoptosis / genetics*
Biomarkers
Disease Models, Animal
Disease Susceptibility
Endoplasmic Reticulum Stress*
Gene Expression Regulation
Genes, Reporter
Inflammation / complications
Inflammation / genetics*
Inflammation / metabolism*
Lipid Metabolism / genetics
Male
Mice
MicroRNAs / genetics*
Non-alcoholic Fatty Liver Disease / etiology*
Non-alcoholic Fatty Liver Disease / metabolism*
Non-alcoholic Fatty Liver Disease / pathology
RNA Interference
Signal Transduction

Substances

Activating Transcription Factor 6
Atf6 protein, mouse
Biomarkers
MIRN149 microRNA, mouse
MicroRNAs