Written by | nagashi
Wine, since the first brewing, has been integrated into the details of people's lives, whether it is sad and happy or clutch, wine is never absent. However, it is worth noting that drinking alcohol is harmful to health, and excessive alcoholism will induce cardiovascular and cerebrovascular diseases, metabolic diseases and nervous system diseases, and even closely related to the occurrence and development of cancer.
Not only that, but drinking alcohol is accompanied by many side effects, such as visual impairment, limb movement incoordination, and motor reflex nerve retardation, so drunk driving is an extremely dangerous behavior. On May 1, 2011, the Eighth Amendment to the Criminal Law of the People's Republic of China formally incorporated drunk driving into the Criminal Law, increasing the punishment for drunk driving.
It's self-evident that alcohol can cause brain function and behavior disorders, but how alcohol does it has yet to be clearly studied.
On March 22, 2021, The team of Professor Li Zhang of the National Institutes of Health's (NIH) Institute of Alcohol Abuse and Alcoholism (NIAAA) published a paper in the journal Nature Metabolism titled Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication Research paper, which was also selected as the cover paper of the current issue.
The study showed that the disorders of balance and motor coordination caused by low doses of alcohol are not mediated by ethanol itself, but by one of its metabolites, acetic acid (that is, acetic acid, the main component of vinegar).
Further research revealed that these acetic acids, which affect the nervous system, are produced by astrocytes in the brain, rather than liver cells previously thought.
Alcoholic beverages are one of the most important drinks, with nearly 2 billion consumers worldwide. But it has to be said that not all people are tolerant to alcohol, and alcohol use disorders are often genetically linked, the most notable of which is a defect in the acetaldehyde dehydrogenase 2 (ALDH2) gene.
ALDH2 is a key enzyme that converts acetaldehyde to acetic acid, so ALDH2 deficiency can lead to elevated blood acetaldehyde levels after drinking alcohol, a blushing reaction even at low doses of alcohol, and this missense mutation of ALDH2 occurs in nearly half of the Asian population.
Many related studies have concluded that the harm of alcohol and its effect on behavior is caused by acetaldehyde, a metabolite in between, while acetic acid has always been considered a harmless alcohol metabolite, and cerebral acetate is thought to be mainly derived from alcohol metabolism in the liver.
Today, the study led by Professor Zhang Li has shattered this understanding.
In this study, the team confirmed through quantitative PCR technology and RNAscope technology that astrocytes in the cerebellum can express ALDH2 and mediate ethanol-induced elevation of cerebellar acetic acid levels, an important brain region for maintaining balance and coordinating body movements.
ALDH2 is specifically expressed in astrocytes of the cerebellum
Not only that, but the researchers also constructed a mouse model of the ALDH2 gene knockout of the liver (Aldh2Hep −/−) or astrocytes (Aldh2Gfap −/−), and the results showed that in Aldh2Gfap −/− mice, acetic acid and GABA (an important inhibitory neurotransmitter) did not increase, indicating that both originated from ALDH2 enzyme activity in astrocytes.
Schematic diagram of the metabolic pathway from ethanol to acetic acid in the liver and brain
The researchers found that acetic acid itself was sufficient to raise GABA levels in mouse brain tissue and mediate ethanol-induced dyskinesia through the GABAergic mechanism, thereby demonstrating a link between ALDH2 in astrocytes and GABA synthesis and its signaling pathways.
More convincingly, in ALDH2 knockout mice of astrocytes, while these mice still exhibited low ethanol-induced temperatures, they unexpectedly showed resistance to alcohol-induced disorders of balance and motor coordination, meaning that ALDH2 of astrocytes was necessary for certain behavioral effects of alcohol.
Aldh2-mediated ethanol metabolism in astrocytes enhances GABA activity levels
In fact, proteases associated with alcohol metabolism, such as ethanol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), are expressed in neuronal and non-neuronal cells throughout the brain. Thus, region-specific ethanol metabolism may be the basis for different behavioral changes caused by ethanol.
More broadly, this study adds to the recognition that astrocytes control neural activity and behavior by synthesizing and releasing GABA into the extracellular environment. However, for now, how ALDH2 and acetic acid affect gaBA synthesis and its signaling pathways remain to be clarified.
Ethanol metabolism in cerebellar astrocytes regulates the association with alcoholism-related sports injuries
All in all, this study suggests that acetic acid is not a harmless alcohol metabolite, and that astrocytes in the cerebellum metabolize ethanol to acetic acid through the ALDH2 enzyme, and that the acetic acid metabolite will raise GABA levels in the cerebellum and induce dyslexia in the body's post-alcohol balance and motor coordination through the GABAergic mechanism.
And, this study also suggests that even metabolites that we consider harmless can be responsible for the body's disorders!
Science should not be bound by "convention", dare to doubt, bold hypothesis, careful verification is the correct scientific concept!
Dr. Jin Shiyun of the Second Affiliated Hospital of Anhui Medical University, Professor Cao Qi of the University of Maryland School of Medicine, and Yang Fanghan of Peking Union Medical College are the co-first authors of the paper, and Professor Zhang Li is the corresponding author of the paper.
bibliography:
https://www.nature.com/articles/s42255-021-00357-z
https://www.nature.com/articles/s42255-021-00355-1