Nature Metabolism: Subverting cognition: The culprit of dizziness and mobility impairment after drinking is not alcohol, but its metabolite acetic acid

Wine, since it was first brewed, has been integrated into the details of people's lives.

Not only that, drinking will also be accompanied by many side effects, such as visual impairment, uncoordinated limb movement, and retardation of motor reflexes.

It is self-evident that alcohol can cause brain function and behavioral disorders, but how alcohol does this has not been studied clearly.

On March 22, 2021, the team of Professor Zhang Li from the National Institutes of Health (NIH) Institute of Alcohol Abuse and Alcoholism (NIAAA) published in the journal Nature Metabolism the title: Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of The research paper of ethanol intoxication, which was also selected as the cover paper of the current issue.

This study shows that the balance and movement coordination disorders caused by low-dose 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 studies have shown that the acetic acid that affects the nervous system is produced by astrocytes in the brain, rather than liver cells as previously thought.

Alcoholic beverages are one of the most important beverages, with nearly 2 billion consumers worldwide.

ALDH2 is a key enzyme that converts acetaldehyde into acetic acid.

Many related studies believe that the harm of alcohol and its effect on behavior are caused by its intermediate metabolite-acetaldehyde.

Today, the research led by Professor Zhang Li has broken this perception.

In this study, the research team confirmed through quantitative PCR technology and RNAscope technology that astrocytes in the cerebellum can express ALDH2 and mediate the ethanol-induced increase in cerebellar acetate levels, while the cerebellum is responsible for maintaining balance and coordinating body movements.

ALDH2 is specifically expressed in astrocytes of the cerebellum

Not only that, the researchers also constructed ALDH2 knockout mouse models of liver (Aldh2Hep?/?) or astrocytes (Aldh2Gfap?/?), and the results showed that in Aldh2Gfap? /? In mice, acetate and GABA (an important inhibitory neurotransmitter) did not increase, indicating that both are derived from the ALDH2 enzyme activity in astrocytes.

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Schematic diagram of the metabolic pathway of ethanol to acetic acid in the liver and brain

The researchers found that acetic acid alone is sufficient to increase GABA levels in mouse brain tissues and mediate alcohol-induced dyskinesia through the GABAergic mechanism, thus proving the existence of ALDH2 and GABA synthesis and its signaling pathways in astrocytes contact.

More convincingly, in the ALDH2 knockout mice of astrocytes, although these mice still exhibited ethanol-induced hypothermia, they unexpectedly showed resistance to alcohol-induced balance and motor coordination disorders.

ALDH2-mediated ethanol metabolism in astrocytes enhances the level of GABA activity

In fact, proteases related to alcohol metabolism, such as alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), are expressed in neurons and non-neuronal cells throughout the brain.

More broadly, this research increases the understanding that astrocytes control neural activity and behavior by synthesizing and releasing GABA into the extracellular environment.

The regulation of ethanol metabolism in cerebellar astrocytes is associated with alcoholism-related sports injuries

All in all, this study shows that acetic acid is not a harmless alcohol metabolite.
Astrocytes in the cerebellum metabolize ethanol to acetic acid through the ALDH2 enzyme.
The acetic acid metabolite will increase the GABA level in the cerebellum, and through the GABAergic mechanism Induce the body's drunken balance and motor coordination disorders.

Moreover, this research also reminds us that even those metabolites that we consider to be harmless may be the culprits of the body's obstacles!

Science should not be constrained by "conventions".
Dare to doubt, make bold assumptions, and carefully verify that are the correct scientific concepts!

Dr.
Jin Shiyun from the Second Affiliated Hospital of Anhui Medical University, Professor Cao Qi from the University of Maryland School of Medicine, and Yang Fanghan from Peking Union Medical College are the co-first authors of the paper, and Professor Zhang Li is the corresponding author of the paper.

Original source:

Jin, S.
, Cao, Q.
, Yang, F.
et al.
Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication.
Nat Metab 3, 337–351 (2021).
https://doi.
org/ 10.
1038/s42255-021-00357-z.