Spermidine Prevents Ethanol and Lipopolysaccharide-Induced Hepatic Injury in Mice.

Raghabendra Adhikari,Joseph Ibrahim,Jaime Arellanes-Robledo,Pamela L Tuma,Ying Cheng,Karina Reyes-Gordillo,Ruchi Shah

doi:10.3390/molecules26061786

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.

Highlights

Alcohol itself is not hepatotoxic, rather, the metabolites and byproducts of its metabolism promote injury [1]
Liver sections from mice treated with both ethanol and LPS displayed lipid droplets, but enhanced injury was observed with apparent areas of necrosis and inflammatory cell infiltration (Figure 1C)
In mice treated with spermidine, liver morphology was virtually indistinguishable from control; no lipid droplet or inflammatory infiltration was observed

Summary

Introduction

Alcohol itself is not hepatotoxic, rather, the metabolites and byproducts of its metabolism promote injury [1]. The accumulated hepatic injury promotes the later stages of alcoholic liver disease, which are characterized by fibrosis and cirrhosis, both of which are largely irreversible and untreatable. A “second hit” must occur for end-stage disease to be realized One such second hit is the bacterial endotoxin, lipopolysaccharide (LPS), that enters the circulation of alcoholics from a leaky gut [3,4]. The accepted “two-hit” model of disease progression posits that the first hit is injury due to ethanol metabolism and the production of reactive metabolites and oxidative stress followed by LPS release that promotes the second hit of nuclear factor κ (NFκB)-mediated pro-inflammatory signaling and the subsequent expression of pro-inflammatory cytokines in Kupffer cells

Methods

Results

Conclusion