Acetate derived from alcohol metabolism directly influences epigenetic regulation in the brain

Triggers in everyday life such as running into a former drinking buddy, walking by a once-familiar bar, and attending social gatherings can all cause recovering alcoholics to "fall off the wagon." About 40 to 60 percent of people who have gone through treatment for substance abuse will experience some kind of relapse, according to the National Institute on Drug Abuse. But what drives the biology behind these cravings has remained largely unknown.

Now, a team led by researchers from the Perelman School of Medicine at the University of Pennsylvania, have shown, in mouse models, how acetate-;a byproduct of the alcohol breakdown produced mostly in the liver-;travels to the brain's learning system and directly alters proteins that regulate DNA function. This impacts how some genes are expressed and ultimately affects how mice behave when given environmental cues to consume alcohol. Their findings were published today in Nature.

It was a huge surprise to us that metabolized alcohol is directly used by the body to add chemicals called acetyl groups to the proteins that package DNA, called histones. To our knowledge, this data provides the first empirical evidence indicating that a portion of acetate derived from alcohol metabolism directly influences epigenetic regulation in the brain."

Shelley Berger, PhD, the Daniel S. Och University Professor in the departments Cell and Developmental Biology and Biology, director of the Penn Epigenetics Institute and study's senior author

It has been known that a major source of acetate in the body comes from the breakdown of alcohol in the liver, which leads to rapidly increased blood acetate. In this study, the team, co-led by Philipp Mews, PhD, a former graduate student in the Berger lab who is now a postdoctoral fellow at Mount Sinai, and Gabor Egervari, MD, PhD, a postdoctoral fellow in Berger's lab, sought to determine whether acetate from alcohol breakdown contributes to rapid histone acetylation in the brain. They did so by using stable-isotope labeling of alcohol to show that alcohol metabolism does, in fact, contribute to this process by directly depositing acetyl groups onto histones via an enzyme called ACSS2.

Authors said that "ACSS2, 'fuels' a whole machinery of gene regulators 'on site' in the nucleus of nerve cells to turn on key memory genes that are important for learning. In fact, Berger and colleagues published findings on ACSS2 in a 2017 Nature paper. In that paper and previous work, the researchers found that ACSS2 is needed to form spatial memories.

In the current study, to better understand how the alcohol-induced changes in gene expression ultimately effect behavior, Berger and her team employed a behavioral test. Mice were exposed to "neutral" stimuli and alcohol reward in distinct compartments, distinguished by environmental cues. After this conditioning period, the researchers measured the preference of the mice by allowing them free access to either compartment, and recording the time spent in both the neutral and alcohol-paired chamber. They found that, as expected, mice with normal ACSS2 activity spent more time in the alcohol compartment following the training period.

To test the importance of ACSS2 in this behavior, researchers reduced the protein level of ACSS2 in a brain region important for learning and memory, and observed that, with lowered ACSS2, there was no preference shown for the alcohol-paired compartment.

"This indicates to us that that alcohol-related memory formation requires ACSS2," Egervari said. "Our molecular and behavioral data, when taken together, establish ACSS2 as a possible intervention target in alcohol use disorder-;in which memory of alcohol-associated environmental cues is a primary driver of craving and relapse even after protracted periods of abstinence."

Importantly, these findings suggest that other external or peripheral sources of physiological acetate – primarily the gut microbiome – may similarly affect central histone acetylation and brain function, which may either control or foster other metabolic syndromes.

In addition to investigating the impact of alcohol consumption on brain changes in adults, the team also looked into the effects of consumption in pregnant mice and thus the impact of alcohol on brain cells in developing mice. In utero, alcohol causes impaired neurodevelopmental gene expression and can elicit numerous alcohol-associated postnatal disease symptoms such as small head size, low body weight, and hyperactivity. And while the number of those affected by fetal alcohol spectrum disorders (FASDs)-;which includes fetal alcohol syndrome-;is unknown, the Centers for Disease Control and Prevention suggests that the full range of FASDs in the United States and some Western European countries could be as high as one to five percent of the population.

In this arm of the study, researchers found that, upon consumption of alcohol, acetate is delivered through the placenta and into the developing fetus. The fetal brains of these mice showed that alcohol exposure on the level of "binge drinking" in the pregnant female resulted in deposition of alcohol-derived acetyl-groups onto histones in fetal brains in early neural development in the mice.

Much like the primary results of the study being useful for the potential treatment of alcohol-use disorder, these results could have implications for understanding and combating fetal alcohol syndrome.

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