Effects of Drp1 Inhibitor Mdivi-1 on Lipopolysaccharide/D-galactosamineInduced Acute Liver Injury and Its Mechanism
XIAO Lidan, TANG Li, YANG Yongqiang, LI Longjiang, HUANG Jiayi, SHEN Yi, ZHANG Li*
The mitochondrial protein Drp1 (dynamin-related protein 1) is a new target for the regulation of apoptosis, and apoptosis is an important feature of acute liver injury. In this study, the selective Drp1 inhibitor Mdivi-1 was used to explore the role of Drp1 in the possible pathophysiology of liver injury and its potential drug target value. In this study, 6-8 week-old male BAlB/c mice were injected intraperitoneally with LPS (lipopolysaccharide)/ D-Gal (D-galactosamine) to induce an acute liver injury model. The experiment was divided into four groups: normal control group (A), Mdivi-1 alone treatment group (B), model group (C), and Mdivi-1 intervention group (D). Mdivi-1 was injected intraperitoneally 30 minutes before LPS/D-Gal exposure. Animals were sacrificed after LPS/ D-Gal injection in 1.5 h or 6.0 h, liver tissue and plasma samples were collected. Histopathological staining, colorimetric detection of plasma transaminase activity, detection of cytokine TNF-α, activity of casepase-3, casepase-8, and casepase-9 and TUNEL technology were used to explore the improvement of liver injury induced by Mdivi-1. The results showed that the pathological changes of liver tissue were observed by HE staining. There was no abnormal liver tissue structure in normal control group and Mdivi-1 alone treatment group. LPS/D-Gal exposure could cause a series of significant histological abnormalities. The degree of liver damage was assessed by measuring the activity of plasma ALT (alanine aminotransferase) and AST (aspartate aminotransferase). The activity of ALT and AST in the Mdivi-1 intervention group was significantly reduced (P<0.05). TNF-α (tumor necrosis factor alpha) levels in plasma were used to assess the degree of inflammatory response. The expression of inflammatory cytokines in the Mdivi-1 intervention group was significantly reduced (P<0.05). Casepase-3, casepase-8, casepase-9 and TUNEL staining were used to assess the degree of tissue apoptosis, and the level of apoptosis in the Mdivi-1 intervention group decreased significant (P<0.05). Therefore, it was concluded that Mdivi-1 intervention could reduce LPS/D-Gal-induced liver tissue lesions, reduce plasma transaminase, down-regulate plasma TNF-α levels, reduce liver casepase-3, casepase-8, casepase-9 activities and reduce the number of TUNEL positive cells. The above data indicated that the Drp1 inhibitor Mdivi-1 could reduce LPS/D-Gal-induced acute liver injury.
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