Hepatocyte-specific ablation of spermine/spermidine-N¹-acetyltransferase gene reduces the severity of CCl₄-induced acute liver injury

Abstract

Activation of spermine/spermidine-N 1 -acetyltransferase (SSAT) leads to DNA damage and growth arrest in mammalian cells, and its ablation reduces the severity of ischemic and endotoxic injuries. Here we have examined the role of SSAT in the pathogenesis of toxic liver injury caused by carbon tetrachloride (CCl 4). The expression and activity of SSAT increase in the liver subsequent to CCl 4 administration. Furthermore, the early liver injury after CCl 4 treatment was significantly attenuated in hepatocyte-specific SSAT knockout mice (Hep-SSAT-Cko) compared with wild-type (WT) mice as determined by the reduced serum alanine aminotransferase levels, decreased hepatic lipid peroxidation, and less severe liver damage. Cytochrome P450 2e1 levels remained comparable in both genotypes, suggesting that SSAT deficiency does not affect the metabolism of CCl 4. Hepatocyte-specific deficiency of SSAT also modulated the induction of cytokines involved in inflammation and repair as well as leukocyte infiltration. In addition, Noxa and activated caspase 3 levels were elevated in the livers of WT compared with Hep-SSAT-Cko mice. Interestingly, the onset of cell proliferation was significantly more robust in the WT compared with Hep-SSAT Cko mice. The inhibition of polyamine oxidases protected the animals against CCl4-induced liver injury. Our studies suggest that while the abrogation of polyamine back conversion or inhibition of polyamine oxidation attenuate the early injury, they may delay the onset of hepatic regeneration. hepatotoxicity; carbon tetrachloride; polyamine POLYAMINES INTERACT WITH NUCLEIC acids and proteins and through these interactions play important roles in gene transcription, signal transduction, and cell proliferation (6,12,14,15,20). The cellular levels of polyamines are tightly regulated through import, export, synthesis and catabolism (Fig. 1). The initial step in polyamine synthesis is the decarboxylation of ornithine by ornithine decarboxylase (ODC) to form putrescine (Put). Sequential addition of aminopropyl residues to Put and spermidine (Spd) lead to the formation of Spd and spermine (Spm). Polyamines are degraded through their back conversion by Spm/Spd-N 1 -acetyltransferase (SSAT) and N 1 -acetylpolyamine oxidase (APAO) or by oxidation of Spm by Spm oxidase (SMO). Oxidation of acetylated Spm and Spd by APAO and Spm by SMO generates cytotoxic molecules such as H 2 O 2 and aldehydes (i.e., 3-aminopropanal and 3-acetoaminopropanal; Fig. 1).The expression and activity of SSAT increases in organs (e.g., liver, kidney, and brain) subjected to ischemia-reperfusion and septic and traumatic injuries (4,35,37,39). The ablation of the SSAT gene reduces the severity of renal and hepatic ischemia-reperfusion and endotoxin-induced renal injuries (35,37). Transgenic animals that express high levels of SSAT develop several pathologies, including skin lesions and pancreatitis (1,24,25). In vitro, expression of SSAT causes oxidative stress, DNA damage, cell cycle arrest, and apoptosis (7, 11). These results sugg...

Myricitrin exhibits antioxidant, anti-inflammatory and antifibrotic activity in carbon tetrachloride-intoxicated mice

“…Several studies suggested that CYP2E1 was degraded during CCl 4 -induced hepatotoxicity [28,29]. Our results showed that the CCl 4 -mediated reduction in CYP2E1 expression was significantly ameliorated by myricitrin, suggesting the suppression of CYP-mediated CCl 4 bioactivation.…”

Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses

“…Notably, p53-mediated ferroptosis in response to ROS stress through SLC7A11 suppression is a recently discovered tumor-suppression mechanism (11). In fact, polyamine metabolism has been implicated in ROS stress response, because the natural polyamine spermine can function as a free radical scavenger, whereas catabolization of polyamine by SAT1 and polyamine oxidase (PAO) gives rise to H 2 O 2 and increase oxidative stress (33)(34)(35). Nevertheless, the cell-death response upon SAT1 expression in the setting of oxidative stress exposure is unexplored.…”

Polyamine catabolism and oxidative damage

“…Ischemia reperfusion injury (IRI), physical trauma, and toxins induce PA catabolism through SSAT and SMOX in multiple organs, leading to tissue damage (73,(97)(98)(99)(100)(101). SSAT, in particular, plays a significant role in promoting kidney and liver damage in IRI (102), and conditional knockout of SSAT in proximal tubule epithelial cells, where the primary effects of IRI manifest, decreases renal damage severity via reductions in both PAOX and SMOX activities.…”