Tag: alcohol-associated liver disease

Categories : Metabolic Disorders Substance UseTags :

GLP-1 Receptor Agonists Protect the Liver During Alcohol Consumption

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GLP-1 receptor agonists are also promising for the treatment of alcohol use disorder and alcohol-associated liver disease, as growing evidence suggests they reduce the motivation to drink alcohol. Now, surprising new findings reveal that the medications may have direct protective effects on the liver as well.

In a new study, published in npj Metabolism Health and Disease, Yale School of Medicine (YSM) researchers found that in mice, GLP-1RAs reduced an enzyme that metabolises alcohol. That, in turn, decreased the production of toxic alcohol metabolites.

“This is the first time that GLP-1 receptor agonists have been shown to regulate alcohol metabolism in the liver,” says principal investigator Wajahat Mehal, MD, professor of medicine (digestive diseases) at YSM. “If you’re taking semaglutide, then your body will likely handle alcohol differently.”

However, because these drugs slowed the metabolism of alcohol, the mice also had higher blood alcohol levels, the researchers found.

“GLP-1 receptor agonists seem to have very similar effects in mice and humans,” says Mehal. “If these results are also reproduced in humans, people using GLP-1 receptor agonists might be drinking an amount of alcohol that does not normally put them above the legal blood alcohol level, but because they are taking this drug, it does.”

Further studies in humans are needed to understand these impacts of GLP-1 receptor agonists more fully, he stresses.

GLP-1 receptor agonists decrease toxic alcohol metabolites

In the study, researchers gave mice either a GLP-1 receptor agonist or a placebo. They observed that mice receiving the medication had decreased levels of a liver enzyme known as Cyp2e1, which breaks down alcohol into a toxic metabolite called acetaldehyde.

“This is significant because alcohol itself is actually not the most toxic molecule to the liver,” explains Mehal. Rather, acetaldehyde is one of the major drivers of alcohol-related harm to the liver. “These drugs are resulting in less acetaldehyde.”

The findings suggest that not only might GLP-1 receptor agonists help the liver by acting on the brain to reduce alcohol consumption, but also through slowing metabolism of alcohol in the liver, and in turn reducing the levels of toxic metabolites.

Ongoing clinical trials are currently testing the benefits of semaglutide for people living with alcohol-induced liver disease. The study suggests that GLP-1 receptor agonists may offer greater benefits to the liver than previously thought, and that the drug may still help patients who are not abstaining from alcohol.

“Even if some individuals don’t reduce their alcohol intake while they’re on a GLP-1 receptor agonist, they will probably still have hepatic protection, because fewer toxic metabolites will be produced in the liver,” Mehal says.

GLP-1 receptor agonists increase blood alcohol concentration

In another experiment, the researchers measured blood alcohol concentrations of mice 30 minutes after giving them alcohol. They found that mice who had received a GLP-1 receptor agonist had higher blood alcohol concentrations compared to controls, and that these levels took longer to drop.

More research is needed to better understand the consequences of elevated blood alcohol levels on the rest of the body, Mehal says.

“If the liver is not metabolizing alcohol as quickly, the alcohol load could be shifted to other organs,” he poses. “Then, not only might people have a high blood alcohol level, but may also experience more cognitive effects like discoordination.”

The number of people taking these drugs is rapidly increasing—as many as one in eight adults in the U.S. have used or are currently using a GLP-1 receptor agonist. Meanwhile, about half of U.S. adults drink alcohol and 6% report drinking heavily.

As the use of these medications for a range of conditions continues to rise, it is increasingly important to study the interactions between these medications and alcohol, Mehal says.

“There already are large numbers of people who are taking GLP-1 receptor agonists and are drinking either social amounts or excess amounts of alcohol,” says Mehal. “We need to know the effects of these drugs in that setting.

Source: Yale School of Medicine

Categories : Substance UseTags :

Long-term Alcohol Use Suspends Liver Cells in Limbo, Preventing Regeneration

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Photo by Pavel Danilyuk on Pexels

Excessive alcohol consumption can disrupt the liver’s unique regenerative abilities by trapping cells in limbo between their functional and regenerative states, even after a patient stops drinking, as described in a new study from researchers at University of Illinois Urbana-Champaign and collaborators.

This in-between state is a result of inflammation disrupting how RNA is spliced during the protein-making process, the researchers found, providing scientists with new treatment pathways to explore for the deadly disease. The researchers published their findings in the journal Nature Communications.

The liver has a remarkable ability to regenerate itself after damage or partial removal. However, it loses that ability in patients with alcohol-associated liver disease – the leading cause of liver-related mortality worldwide, resulting in roughly 3 million deaths annually.

“We knew that the liver stops functioning and stops regenerating in patients with alcohol-related hepatitis and cirrhosis, even when a patient has discontinued consuming alcohol, but we didn’t know why,” said U. of I. biochemistry professor Auinash Kalsotra, who co-led the study with Duke University School of Medicine professor Anna Mae Diehl. “The only real life-saving treatment option once a patient reaches the liver failure stage in those diseases is transplantation. But if we understood why these livers were failing, maybe we could intervene.”

Both the Kalsotra and Diehl labs havestudied the molecular and cellular underpinnings of liver regeneration. Over the last five years, they found that in order to regenerate, liver cells reprogram their gene expression to revert to fetal-like progenitor cells, multiply and then reverse the process back to become mature functioning cells again. Armed with this knowledge, the group turned to the question of how those mechanisms were disrupted in alcohol-associated liver disease.

The researchers compared samples of healthy livers and samples of livers with alcohol-associated hepatitis or cirrhosis obtained from Johns Hopkins University Hospital through an initiative supported by the National Institute for Alcohol Abuse and Alcoholism, part of the National Institutes of Health.

The first thing the researchers noticed in diseased livers was that, although damaged cells had begun the process of reverting to the regenerative state, they did not complete the process and instead remained in transitional limbo.

“They are neither functional adult cells nor proliferative progenitor cells. Since they are not functioning, more pressure builds on the remaining cells. So they try to regenerate, and they’re all ending up in this unproductive quasi-progenitor state, and that’s what is causing liver failure,” said U. of I. graduate students Ullas Chembazhi and Sushant Bangru, the co-first authors of the study.

To figure out why the cells were getting stuck in this state, the team investigated which proteins were being made by the liver cells and, in turn, the RNA molecules carrying the instructions for those proteins from the DNA to the cell’s protein-building machinery.

While most studies focus only on the total amounts of RNA or protein in a cell, Kalsotra’s team used deep RNA sequencing technology and computational analyses to zoom in on the splicing of RNA fragments, a key step in stitching together different parts of genetic instructions to make proteins.

“In comparing the samples, we saw RNA was getting mis-spliced broadly in alcohol-related liver disease, across thousands of genes, and it was affecting major functions of proteins,” said Kalsotra.

The researchers found a possible driver of the RNA mis-splicing: Alcohol-damaged liver cells had a deficiency of the protein ESRP2, which binds to RNA to splice it properly.  

“Proteins function at a very specific place in the cell, and that is directed by sequences within the protein that take the protein to that particular spot. We found that, in many cases, the sequence that dictates where the protein localizes within a cell was mis-spliced. That’s why it was important that we did the multiple analyses we did,” said Kalsotra. “There was the same amount of RNA and protein, but the protein was not at the right place to function. Due to mis-splicing, key proteins that are required for productive liver regeneration were getting stuck in the cytoplasm, when they needed to be in the nucleus.”

To verify that ESRP2 deficiency was a likely culprit, the researchers studied mice without the gene that produces ESRP2. They displayed similar liver damage and regeneration failure to that seen in patients with advanced alcohol-related hepatitis.

But why was ESRP2 missing from liver cells from patients with alcohol-related hepatitis? Upon investigation, the researchers found that liver support cells and immune cells, drawn to the liver tissue damaged by alcohol processing, released high amounts of inflammatory and growth factors. Those factors suppress ESRP2 production and activity.

To verify this finding, the researchers treated liver cell cultures with a molecule that inhibits the receptor for one of the inflammation-promoting factors. ESRP2 levels recovered and splicing activity was corrected, pointing to the pathway as a possible treatment target.

“I’m hopeful these findings will become a launching pad for future clinical studies. We can use these mis-spliced RNAs as diagnostic markers or develop treatments that can curb the inflammation. And if we can correct the splicing defects, then maybe we can improve recovery and restore damaged livers,” Kalsotra said.

Source: University of Illinois Urbana-Champaign