Molecular pathological mechanism of liver metabolic disorder in mice with severe spinal muscular atrophy.
10.12122/j.issn.1673-4254.2023.05.22
- Author:
Lihe LIU
1
;
Mingrui ZHU
1
;
Yifan WANG
1
;
Bo WAN
1
;
Zhi JIANG
1
Author Information
1. Suzhou Medical College of Soochow University, Suzhou 215000, China.
- Publication Type:Journal Article
- Keywords:
liver metabolism;
mice;
molecular pathological mechanism;
spinal muscular atrophy
- MeSH:
Mice;
Animals;
PPAR alpha;
Liver Diseases;
Muscular Atrophy, Spinal/genetics*;
Mice, Transgenic;
Body Weight;
Glucose
- From:
Journal of Southern Medical University
2023;43(5):852-858
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To explore the molecular pathological mechanism of liver metabolic disorder in severe spinal muscular atrophy (SMA).
METHODS:The transgenic mice with type Ⅰ SMA (Smn-/- SMN20tg/2tg) and littermate control mice (Smn+/- SMN20tg/2tg) were observed for milk suckling behavior and body weight changes after birth. The mice with type Ⅰ SMA mice were given an intraperitoneal injection of 20% glucose solution or saline (15 μL/12 h), and their survival time was recorded. GO enrichment analysis was performed using the RNA-Seq data of the liver of type Ⅰ SMA and littermate control mice, and the results were verified using quantitative real-time PCR. Bisulfite sequencing was performed to examine CpG island methylation level in Fasn gene promoter region in the liver of the neonatal mice.
RESULTS:The neonatal mice with type Ⅰ SMA showed normal milk suckling behavior but had lower body weight than the littermate control mice on the second day after birth. Intraperitoneal injection of glucose solution every 12 h significantly improved the median survival time of type Ⅰ SMA mice from 9±1.3 to 11± 1.5 days (P < 0.05). Analysis of the RNA-Seq data of the liver showed that the expression of the target genes of PPARα related to lipid metabolism and mitochondrial β oxidation were down-regulated in the liver of type Ⅰ SMA mice. Type Ⅰ SMA mice had higher methylation level of the Fasn promoter region in the liver than the littermate control mice (76.44% vs 58.67%). In primary cultures of hepatocytes from type Ⅰ SMA mice, treatment with 5-AzaC significantly up-regulated the expressions of the genes related to lipid metabolism by over 1 fold (P < 0.01).
CONCLUSION:Type Ⅰ SMA mice have liver metabolic disorder, and the down-regulation of the target genes of PPARα related to lipid and glucose metabolism due to persistent DNA methylation contributes to the progression of SMA.
