Fisetin supplementation protects liver from damage caused by binge alcohol consumption

The liver is the bodies largest internal organ consisting out of roughly 360B cells.  It has 500 different roles and tasks. One of the liver’s most important tasks is to break down food and convert it into energy when you need it. Your liver also helps the body to get rid of waste products and plays a vital role in fighting infections, particularly in the bowel.

When the liver is damaged, generally it will not be noticed until things get serious. Drinking alcohol can increase the risk of developing liver disease and cause irreparable damage to this very important part of the body.

Alcohol-related liver disease accounts for well over a third (37%) of liver disease deaths. And figures show victims are getting younger – more than one in 10 of deaths of people in their 40s are from liver disease, most of them from alcoholic liver disease. Typical alcoholic liver damages are hepatic steatosis (fatty liver disease), fibrosis and cirrhosis.

Studies on alcohol consumption revealed that generation of reactive oxygen species (ROS) and enhancement of lipid peroxidation as a result of alcohol metabolism are the key causes in the initiation of acute liver injury. The alcohol metabolite acetaldehyde is found to be responsible for the production of ROS, causing oxidative stress, endoplasmic reticulum stress, fibrosis and eventually leading to cirrhosis in the liver. Specific classes of enzymes, matrix metalloproteinases (MMPs) are found to be involved in the hepatic regeneration and in the remodelling of extracellular matrix (ECM) by causing degradation of its components like gelatin, fibronectin and collagen. It is also reported that alcohol intoxication leads to an increase in the expression of transcription factor nuclear factor-kappa B (NF-κB), which is involved in the initiation of the inflammatory cascade.

Endogenous antioxidants, such as GSH and its catalysed enzymes (glutathione S-transferase, glutathione reductase, and glutathione peroxidase) play an important role in the detoxification and scavenging of ROS and its intermediates and protect the cells from oxidative injury. Superoxide dismutase is the enzyme involved in the dismutation of the superoxide radical, whereas catalase is involved in the decomposition of H2O2.

Fisetin is known to possess antioxidant, anti-inflammatory, anticancer, antihyperlipidaemic, and neuroprotective properties. It has been shown that administration of fisetin restores antioxidant status and attenuates apoptotic protein expressions in kidneys and brain. Fisetin has also been found to protect the liver by attenuating oxidative stress during streptozotocin-induced hyperglycaemia. The researchers that conducted this study hypothesised that fisetin administration may have beneficial effects against alcohol-induced acute liver injury.

To test this, five groups consisting each out of 8 mice (C57BL/6) were treated with different length and dose of fisetin for several days as pre-treatment (or control substance) followed by an alcohol administration resembling heavy drinking behavior. The pre-treament happened over several days with dosing at either 5 or 10 mg/kg. Afterwards liver function, oxidative stress, histological changes, mitochondrial function, pro-inflammatory markers, collagen content, and matrix metalloproteinases were assessed.

In the alcohol only treated mice the researchers observed upregulation of HO-1 expression and the reduced activity of NQO-1 in the liver tissues. Hepatic damage was also confirmed by the morphological and histopathological changes observed in the liver tissue. The alcohol administration caused an increase in the collagen levels, vacuolisation and cellular degeneration and a mild infiltration of inflammatory cells and fibrotic changes in the periportal region of the liver tissue. It also caused a significant increase in the oxidative stress markers, disturbed the mitochondrial function, matrix metalloproteinases activities and also induced histological changes in liver tissue.

Pre-treatment with fisetin restored the mitochondrial respiratory enzyme activities and attenuated the mitochondrial damage. Fisetin administration also recovered the alcohol-induced histological alterations, antioxidants defences, NF-κB expression and stabilised the matrix metalloproteinases (MMPs) activity in the liver tissue.

The dosing, as mentioned earlier, was upto 10mg/Kg/day. Using FDA specified guidelines we can calculate the Human Equivalent Dose (HED) for the diet given to the mice. We find a HED of approx. 0,8mg/kg. Or approximately 60mg daily fisetin dose for a person weighing 70kg. Typical supplements on the market have serving sizes of 100mg.

Overall it can be concluded that fisetin has the potential to ameliorate alcohol-induced hepatic damage and may be used as part of a treatment strategy for alcohol-induced hepatotoxicity. While the author discourages excessive alcohol use the study outcome does suggest that fisetin supplementation during the days before a night out may be a sensible strategy to protect the liver from drinking alcohol.

You can find the study here. It is also notable that fisetin has also been observed to be effective against fibrosis in lung disease.

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