AMPK dependent protective effects of metformin on tumor necrosis factor-induced apoptotic liver injury.
Tumor necrosis factor α (TNF-α)-induced cellular apoptosis represents a common pathological mechanism underlying the progression of various liver disorders. Recently studies revealed that the anti-diabetic metformin provided protective benefits in several animal models of liver injury. In the present study, the potential modulatory effects of metformin on TNF-α-dependent apoptotic liver damage was investigated in mice with TNF-α/d-galactosamine (D-Gal)-induced liver injury. The results indicated that treatment with metformin significantly suppressed the elevation of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the activation of caspase cascade and the induction of cleaved caspase-3. Morphological analysis showed that metformin alleviated histopathological abnormalities and reduced TUNEL-positive apoptotic cells. Co-administration of the AMPK inhibitor compound C completely abolished the inhibitory effects of metformin on caspase cascade activation, significantly reversed the beneficial effects of metformin on histopathological abnormalities and hepatocytes apoptosis, and partially abolished the suppressive effects of metformin on plasma ALT elevation. These data indicated that metformin effectively alleviated TNF-α/D-Gal-induced apoptotic liver injury and these beneficial effects were at least partially mediated by AMPK.
Department of Pathogenic Biology, Chongqing Medical University, Chongqing, China.
Lu
L
Cai
Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
Kai
K
Hu
Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
Ling
L
Lin
Department of Physiology, Chongqing Medical University, Chongqing, China.
Qing
Q
Ai
Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
Pu
P
Ge
Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
Yiqing
Y
Liu
Hospital of Chongqing University of Arts and Sciences, Chongqing, China.
Jie
J
Dai
Department of Pathogenic Biology, Chongqing Medical University, Chongqing, China. Electronic address: yebina@sohu.com.
Bin
B
Ye
Department of Pathophysiology, Chongqing Medical University, Chongqing, China. Electronic address: zhangli@cqmu.edu.cn.
Li
L
Zhang
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha
D014409:Tumor Necrosis Factor-alpha; D008687:Metformin
AMP-activated protein kinase; Apoptosis; Liver injury; Metformin; Tumor necrosis factor α