Spermidine Prevents Ethanol and Lipopolysaccharide-Induced Hepatic Injury in Mice

Abstract

To date, there is no effective treatment for alcoholic liver disease, despite its prevalence world-wide. Because alcohol consumption is associated with oxidative stress-induced liver injury and pro-inflammatory responses, naturally occurring antioxidants and/or anti-inflammatories may be potential therapeutics. Spermidine is an abundant, ubiquitous polyamine that has been found to display strong antioxidant and anti-inflammatory properties. To further investigate whether spermidine is an effective intervention for alcohol-induced liver disease, we examined its hepatoprotective properties using a two-hit, chronic ethanol and acute lipopolysaccharide (LPS)-induced mouse model of liver injury. We determined that spermidine administration prevented ethanol and LPS-induced increases in liver injury using plasma ALT as a readout. Furthermore, histological analysis of tissue from control and treated animals revealed that the pathology associated with ethanol and LPS treatment was prevented in mice additionally treated with spermidine. As predicted, spermidine also prevented ethanol and LPS-induced oxidative stress by decreasing the levels of both reactive oxygen species (ROS) and lipid peroxidation. We further determined that spermidine treatment prevented the nuclear translocation of nuclear factor κB (NFκB) by blocking the phosphorylation of the inhibitory protein, IκB, thereby preventing expression of pro-inflammatory cytokines. Finally, by measuring expression of known markers of hepatic stellate cell activation and monitoring collagen deposition, we observed that spermidine also prevented alcohol and LPS-induced hepatic fibrosis. Together, our results indicate that spermidine is an antioxidant thereby conferring anti-inflammatory and anti-fibrotic effects associated with alcoholic liver injury.

The Impact of Spermidine on C2C12 Myoblasts Proliferation, Redox Status and Polyamines Metabolism under H2O2 Exposure

“…AG treatment did not show any effect on the parameters analyzed in our experimental model. Studies from literature performed in vivo and on other cellular models showed that spermidine effectively plays a role in promoting proliferation [ 58 , 59 , 60 ] and as an antioxidant molecule [ 61 , 62 , 63 ], but our data showed that these effects are only detectable when Spd is in combination with AG.…”

Advancements in the Alcohol-Associated Liver Disease Model

“…When the liver is damaged, alcohol drinkers are more likely to develop fibrosis and cirrhosis [ 203 , 204 ]. Correspondingly, when rodents receive a second hit other than alcohol, liver fibrosis and cirrhosis will also appear in the liver [ 15 , 129 , 132 , 133 , 138 , 139 ]. This is also why patients with end-stage ALD usually have end-stage viral hepatitis, diabetes, and other comorbidities [ 15 ].…”

“…In another model, ALT levels were also significantly increased after the mice were administered an LDE diet for 4 weeks, followed by one intragastric administration of ethanol (5% v / v ) and an intraperitoneal injection of LPS (2 mg/kg). Mouse liver sections also showed lipid droplet accumulation and enhanced liver damage, with distinct areas of necrosis and inflammatory cell infiltration [ 132 ]. In conclusion, the LPS plus ethanol model can induce significant lipid accumulation, inflammation, and liver damage in rodents in a short period of time [ 146 ].…”

A comprehensive review of spermidine: Safety, health effects, absorption and metabolism, food materials evaluation, physical and chemical processing, and bioprocessing

“…As an antioxidant, spermidine also conferred potent anti‐inflammatory effects in the instances of liver injury, colitis, and respiratory inflammation (Adhikari et al., 2021; Liu et al., 2020; Ma et al., 2021). In a mouse model, ethanol‐ and LPS‐induced liver injuries and oxidative stresses were prevented by spermidine administration, which might be due to reductions in reactive oxygen species and lipid peroxidation by spermidine.…”

“…In a mouse model, ethanol‐ and LPS‐induced liver injuries and oxidative stresses were prevented by spermidine administration, which might be due to reductions in reactive oxygen species and lipid peroxidation by spermidine. Moreover, gene expression analysis showed that spermidine inhibited the formation of proinflammatory cytokines and hepatic fibrosis (Adhikari et al., 2021). Spermidine also displayed protective effects against dextran sulfate sodium‐induced colitis in mice (Ma et al., 2021).…”