Journal
MOLECULES
Volume 26, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/molecules26061786
Keywords
alcoholic liver disease; hepatic stellate cell activation; fibrosis; oxidative stress; spermidine
Funding
- National Institutes of Health [R01 AA017626, K01 AA025140-01 400]
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This study found that spermidine can prevent the occurrence of alcoholic liver disease, inhibit liver injury and oxidative stress, reduce nuclear translocation of nuclear factor kappa B, suppress the production of pro-inflammatory cytokines, and ultimately prevent hepatic fibrosis.
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 kappa B (NF kappa B) by blocking the phosphorylation of the inhibitory protein, I kappa B, 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.
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