How a common gene mutation increases liver disease risk

Researchers at Osaka Metropolitan University have identified the mechanism by which a common genetic mutation increases liver disease risk. Published in the journal Free Radical Biology and Medicine, their findings suggest that healthy choices, such as increasing antioxidants and limiting exposure to smoke, may reduce the risk of this disease.

Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme that detoxifies harmful aldehydes produced in the body. While it is best known for metabolising acetaldehyde — an aldehyde increased by drinking — it also plays a role in detoxifying other harmful aldehydes, including acrolein. Acrolein is a highly reactive aldehyde produced by environmental exposure to pollutants such as cigarette smoke. It damages proteins, DNA and lipids, contributing to cardiovascular disease, neurodegeneration and other conditions.

Some East Asians, including about 40% of Japanese people, have a genetic mutation (ALDH2*2) that impairs the function of ALDH2. Carriers of the mutation have an increased risk of oesophageal cancer, especially among heavy drinkers and smokers.

To understand how acute liver injury occurs in living organisms when aldehyde detoxification is impaired, a research group led by Osaka Associate Professor Takeshi Izawa and graduate student Yuki Takami used knock-in mice. These mice are bred to reproduce the dysfunction of the ALDH2 enzyme seen in human ALDH2*2 carriers, making them useful for modelling the processes that lead to liver disease in humans and studying the changes that occur when aldehydes are rapidly produced in the body.

The researchers used allyl alcohol, an alcohol that is metabolised into acrolein in the liver. They found that increased levels of acrolein coincided with the level of multiple aldehydes rapidly increasing in the blood, a phenomenon they named an ‘aldehyde storm’. This subsequently causes aldehydes to accumulate in the liver, causing severe liver damage. Their mechanism suggests the damage that can be caused in people after exposure to high levels of acrolein, especially in those with the ALDH2*2 gene variant.

“The exposure level of acrolein used in this study clearly exceeds that of smoking; therefore, the risk of severe liver damage like that reported in this paper occurring by smoking only is low,” Izawa said. “Instead, it is likely that the risk is higher in patients receiving anticancer drugs, such as cyclophosphamide, which is metabolised to acrolein in the body.”

Typically, acrolein is detoxified by the antioxidant glutathione; however, this did not happen in the mice. Instead, the researchers found that the levels of glutathione in the liver were severely depleted, indicating an inverse association with the aldehyde storm. Glutathione also suppresses oxidative stress and, accordingly, they found that the glutathione depletion promoted oxidative stress in the liver, leading to ferroptosis, a type of cell death. The researchers found evidence of tissue damage across organs, with the liver being the most severely affected.

“We identified for the first time the close relationship among aldehyde metabolism, redox balance and the ferroptosis pathway,” Takami said.

The team’s findings may also be relevant to people who carry the ALDH2*2 gene variant; these people typically have a reduced ability to break down aldehydes from alcohol, certain foods and environmental chemicals. In these individuals, the liver’s antioxidant defences can be overwhelmed by sudden increases in aldehyde levels, leading to cell death and more severe liver injury. The findings suggest that the aldehyde storm is a key part of this process; it is therefore important that people with this variant avoid high aldehyde exposure, support their antioxidant system through a healthy diet, and monitor their liver health.

“Acrolein is also found in electronic cigarette smoke and as a metabolite of anticancer drugs,” Izawa said. “The results of this study suggest that ALDH2*2 carriers may be at health risk from daily exposure to aldehydes caused by smoking and in certain medications.

“Going forward, we plan to investigate other health effects of chronic exposure to aldehydes in ALDH2*2 carriers, particularly their involvement in cancer.”

Image credit: Osaka Metropolitan University.