Submit Data |  Help |  Video Tutorials |  News |  Publications |  FTP Download |  REST API |  Citing RGD |  Contact   

MicroRNA-29a mitigation of endoplasmic reticulum and autophagy aberrance counteracts in obstructive jaundice-induced fibrosis in mice.

Authors: Huang, Ying-Hsien  Yang, Ya-Ling  Huang, Fu-Chen  Tiao, Mao-Meng  Lin, Yen-Cheng  Tsai, Ming-Horng  Wang, Feng-Sheng 
Citation: Huang YH, etal., Exp Biol Med (Maywood). 2018 Jan;243(1):13-21. doi: 10.1177/1535370217741500. Epub 2017 Nov 6.
Pubmed: (View Article at PubMed) PMID:29105510
DOI: Full-text: DOI:10.1177/1535370217741500

Hepatic fibrosis was caused by a number of signaling pathways that damage liver integrity. We have previously shown that microRNA-29a (miR-29a) protects against liver fibrosis. Aberrant endoplasmic reticulum (ER) and autophagy function reportedly exaggerate hepatic disorders. The aim of this study was to characterize the biological influence of miR-29a on ER function in injured livers with bile duct ligation (BDL). We performed BDL on miR-29a transgenic mice (miR-29aTg) and wild-type mice to induce cholestatic liver injury. Rat T6 cells were transfected with miR-29a mimic and tunicamycin. Compared to the wild-type mice, the BDL deterioration of liver function in terms of total bilirubin, alanine transaminase, and aspartate transaminase activity in the miR-29aTg mice was significantly reduced. Affected livers in the miR-29aTg mice demonstrated a slight fibrotic matrix formation. miR-29a over-expression reduced the BDL disturbance of the expressions of inositol-requiring kinase 1alpha, double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase, spliced-X-box binding protein 1 (sXBP1), CCAAT/enhancer-binding protein homologous protein (CHOP), ULK, LC3BII, p62, and cleaved caspase-8, 9 and 3. In vitro, T6 cells exposed to tunicamycin by increasing abundances of CHOP, sXBP1, cleaved caspase-3, and LC3BII were diminished in the cell cultures transfected with the miR-29a mimic. On the other hand, we observed that miR-29a signaling protected liver tissues from BDL-mediated metabolic dysfunction and excessive fibrosis histopathology. This study provides new molecular insight into the miR-29a stabilization of ER integrity that slows the progression of cholestatic liver deterioration. Impact statement Long-term hepatic damage caused by hepatitis and cholestasis can accelerate fibrosis matrix over-production, which is a harmful process attributed to the dysregulation of a number of cellular and molecular events. The purpose of this study is to characterize the biological influence of miR-29a on endoplasmic reticulum (ER) function in bile duct ligation (BDL)-injured livers. To the best of our knowledge, this report is the first demonstration that miR-29a over-expression diminishes BDL provocation of ER stress (unfolded protein response, UPR) effector protein expression. This work also demonstrates that miR-29a decreased caspases protein expression in cholestatic livers, while an increase in miR-29a function reduced sXBP1 and CHOP expressions in T6 cells in mice. Analyses of this study highlight that controlling miR-29a signaling can serve as an innovative strategy in the future for microRNA regulation of ER homeostasis to combat cholestasis induction hepatic disorders.

Annotation

Disease Annotations
Objects Annotated

Additional Information

 
RGD Object Information
RGD ID: 13782297
Created: 2018-09-04
Species: All species
Last Modified: 2018-09-04
Status: ACTIVE



NHLBI Logo

RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.