Hepatoprotective effects of sea cucumber ether-phospholipids against alcohol-induced lipid metabolic dysregulation and oxidative stress in mice.

Wang X, Wang Y, Liu Y, Cong P, Xu J, and Xue C. (2022) Hepatoprotective effects of sea cucumber ether-phospholipids against alcohol-induced lipid metabolic dysregulation and oxidative stress in mice. Food & Function

Alcoholic liver disease (ALD) is caused by excessive alcohol consumption. ALD results in a spectrum of histological lesions such as liver steatosis which is excessive fat accumulation, or cirrhosis, degeneration of the liver. The progression of the disease is influenced by drinking pattern, genetic factors, and environmental factors, but the damage to the liver is caused by cell injury, oxidative stress, disrupting hepatocyte metabolism, liver inflammation, and impaired regeneration. Although alcohol abstinence is essential to control ALD, if the disease has progressed to hepatitis or advanced ALD, a transport and additional medications are needed. The medications such as nutritional support, anti-oxidant drugs, and anti-inflammatory drugs are necessary, but their long-term use has harmful effects in the patients. Because of this, a search for a more natural solution that can treat steatosis and reduce oxidative stress is ongoing. Wang et al investigated the use of plasmalogens, a class of phospholipid that contains a vinyl-ether bond at the sn-2 position as a treatment for ALD. 

Plasmalogens were extracted from fresh sea cucumber, a species known to be abundant in ether phospholipids and treated six-week-old C57BL/6M male mice. Five groups treated for 35 days were analyzed: one fed a normal diet, one was administered an ethanol liquid diet at three stages to progressively receive more ethanol over the 5 weeks, one was also receiving the ethanol diet and an ethanolamine plasmalogen (PlsEtn) treatment, one was fed the ethanol diet and received a choline plasmalogen (PlsCho) treatment, and the last received ethanol and N-acetyl cysteine (NAC). NAC has shown liver protection in mouse models of liver diseases and has antioxidant properties. The liver index was found to be increased and the weight decreased in the ethanol treated groups compared to the control group, but neither plasmalogen treatment significantly reduced the liver index. To analyze alcohol-induced injury of the liver, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were determined. The levels of AST and ALT in the ethanol-treated group were elevated compared to the control group, but interestingly, the plasmalogen treatments significantly reduced the activity of both enzymes, indicating lower levels of liver injury, while the group that received NAC did not show any detectable effect.

A common effect of excess alcohol consumption is liver steatosis, or fatty liver disease, therefore histology was used to measure lipid accumulation through hematoxylin and eosin (H&E) and Oil red O staining. The PlsEtn treatment was more effective than either the PlsCho or NAC treatments at alleviating the liver steatosis seen through the recovery of hepatic lobules and cells. The ethanol treatment demonstrated more lipid droplet accumulation than the control group, and this accumulation was also reduced in the PlsEtn treated group.

Each vinyl-ether bond in plasmalogens is known to scavenge two radical oxygen species (ROS), thus reducing oxidative stress. To determine if either plasmalogen treatment altered the level of oxidative stress and mitochondrial function in the ethanol treated mice, levels of ROS, malondialdehyde (MDA), and superoxide dismutase (SOD) were measured. The ethanol treated mice showed increase levels of ROS and MDA and decreased SOD activity. The PlsEtn treatment was most effective at regulating mitochondrial function through producing the lowest ROS levels, even compared to the control, mitochondiral membrane potential being returned to control levels, and MDA returning to control levels. PlsCho and NAC treatments demonstrated some aid in lowering ROS and MDA levels and increasing mitochondrial membrane potentials, but in all cases, NAC was worse than PlsCho. PlsEtn, PlsCho, and NAC did not alter SOD activity.

As there is no ideal treatment plan for people with ALD, Wang et al were interested in determining whether a plasmalogen treatment could prove effective at recovering liver injury and reducing the effects of oxidative stress. In addition, they determined if the polar head group at sn-1 on plasmalogens makes a difference in these effects and how they compared to NAC. Although both treatment groups showed improvements compared to the group that only was treated with ethanol, PlsEtn was more effective overall. The abundance of different classes of plasmalogens often differs in a tissue-dependent matter and these results could indicate that the ethanolamine head group is more successful in the liver than the choline headgroup, therefore should be chosen for a liver-targeted treatment. This study also demonstrated that the current drug used in people with ALD, NAC, is not superior to the effects of PlsEtn or PlsCho. Further work looking at a longer treatment could show whether these results could improve further or whether a pre-treatment with PlsEtn would inhibit any of the effects of ALD from occurring or if it could slow down progression.