Role of AMPKα2 in regulating the IRE1α-JNK pathway in metabolic dysfunction-associated fatty liver disease.
10.11817/j.issn.1672-7347.2024.240474
- Author:
Shujie ZHAO
1
,
2
,
3
;
Weilun FANG
4
;
Yu WEI
1
;
Jiahui MENG
1
;
Qiao JIN
5
;
Weijin FANG
1
Author Information
1. Department of Pharmacy, Third Xiangya Hospital, Central South University, Changsha
2. zhaoshujie1999@
3. com.
4. Department of Oncology, Third Xiangya Hospital, Central South University, Changsha 410013, China.
5. Department of Oncology, Third Xiangya Hospital, Central South University, Changsha 410013, China. 352205906@qq.com.
- Publication Type:Journal Article
- Keywords:
adenosine 5’-monophosphate-activated protein kinase α2;
autophagy;
endoplasmic reticulum stress;
ferroptosis;
metabolic dysfunction-associated fatty liver disease
- MeSH:
Animals;
AMP-Activated Protein Kinases/physiology*;
Protein Serine-Threonine Kinases/metabolism*;
Mice, Knockout;
Diet, High-Fat/adverse effects*;
Mice, Inbred C57BL;
Mice;
Endoplasmic Reticulum Stress;
Endoribonucleases/metabolism*;
Male;
Liver/pathology*;
Non-alcoholic Fatty Liver Disease/metabolism*;
MAP Kinase Signaling System/physiology*;
Fatty Liver/metabolism*;
Signal Transduction
- From:
Journal of Central South University(Medical Sciences)
2024;49(12):1891-1901
- CountryChina
- Language:English
-
Abstract:
OBJECTIVES:Over 25% of the global population is affected by metabolic dysfunction-associated fatty liver disease (MAFLD), yet its pathogenesis remains unclear. Endoplasmic reticulum stress (ERS) may be involved in the onset and progression of MAFLD. Adenosine 5'-monophosphate-activated protein kinase α2 (AMPKα2), a key regulator of hepatic energy metabolism, may influence MAFLD development via ERS modulation. This study aims to investigate the role of AMPKα2 in a high-fat diet-induced MAFLD mouse model and its regulatory effect on the inositol-requiring enzyme 1 alpha (IRE1α)-c-Jun N-terminal kinase (JNK) signaling pathway.
METHODS:Liver-specific AMPKα2 knockout mice on a C57BL/6 background were generated and subjected to MAFLD induction. Mice were divided into four groups: wild-type control (WT+Chow, basic diet for 12 weeks), wild-type high-fat diet (WT+HFD, high-fat diet for 12 weeks), AMPKα2 knockout control (AMPKα2 KO+Chow), and AMPKα2 knockout high-fat diet (AMPKα2 KO+HFD). Blood glucose, lipid levels, and liver function were assessed post-treatment. Liver histology was analyzed using Oil Red O, hematoxylin-eosin, Masson, and Sirius Red staining. Western blotting was used to evaluate the expression of AMPKα2, ERS markers, autophagy, apoptosis, and ferroptosis-related proteins.
RESULTS:Compared with the WT+Chow group, the WT+HFD group showed significantly elevated blood glucose, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels (all P<0.01); histological analyses revealed hepatic steatosis, vacuolization, and fibrosis, with a significantly increased non-alcoholic steatohepatitis activity score (NAS) (P<0.001). Phosphorylated IRE1α and the autophagy marker microtubule-associated protein light chain (LC) 3II/LC3I were markedly upregulated, while apoptotic proteins (Cleaved-Caspase 3, BAX, Bcl-2) and ferroptosis markers (SLC7A11, GPX4) showed no significant change (P>0.05). In the AMPKα2 KO+HFD group, blood glucose, ALT, and AST levels were significantly reduced compared to the WT+HFD group. Histological improvements were observed with reduced vacuolization and lipid accumulation. Expression of p-IRE1α, JNK, and LC3II/LC3I was significantly decreased (P<0.05).
CONCLUSIONS:Hepatic AMPKα2 knockout alleviates high-fat induced MAFLD, potentially by inhibiting the IRE1α-JNK pathway and reducing autophagy.
