Fatty liver disease is one of the most common chronic liver conditions, affecting more than one in three people in the United States.
Also known as Metabolic Dysfunction Associated Steatotic Liver Disease, it is linked to serious health risks such as type 2 diabetes, cirrhosis, and liver cancer.
While unhealthy diets and obesity are major drivers of the disease, alcohol consumption also plays a significant role.
Now, researchers at the Mayo Clinic have uncovered a new reason why excessive drinking damages the liver.
Their study, published in the Journal of Cell Biology, reveals that alcohol interferes with an important enzyme responsible for recycling damaged proteins.
Without this enzyme working properly, fat builds up in liver cells, setting the stage for fatty liver disease.
The liver is the body’s main filter, processing almost everything we eat, drink, or absorb. Liver cells, called hepatocytes, handle the enormous task of sorting, recycling, and releasing proteins.
They also manage fats that enter from the gut, storing them inside structures known as lipid droplets. These droplets normally serve as an energy reserve, but when they become too abundant, they lead to fatty liver disease.
The researchers focused on a crucial enzyme called valosin-containing protein (VCP), which plays a central role in recycling unwanted proteins. VCP is found in cells throughout the body, but in the liver it helps regulate fat storage. Under normal conditions, VCP keeps a protein called HSD17β13 under control. If this protein builds up on lipid droplets, fat accumulates inside the liver cells.
“What we found was surprising,” said Dr. Mark McNiven, senior author of the study. “Excessive alcohol removes VCP from the surface of the lipid droplet, which allows HSD17β13 to accumulate. As a result, fat content in the liver balloons and contributes to fatty liver disease.”
Using advanced imaging techniques, the researchers were able to watch VCP at work. They saw it partner with a helper protein to deliver damaged proteins to an organelle called a lysosome, where the proteins were broken down and recycled. “It was astounding to see this process unfold,” said lead author Dr. Sandhya Sen, a Mayo Clinic research fellow. “Every experiment confirmed that VCP is directly involved in moving HSD17β13 from the lipid droplet to the lysosome.”
These findings highlight HSD17β13 as a promising target for new therapies to prevent or treat fatty liver disease. They also suggest that some people may be more vulnerable to alcohol-related liver damage if this protein recycling system is already impaired.
“This study deepens our understanding of how fat builds up in the liver and how alcohol accelerates the process,” Dr. McNiven explained. “It also opens the door to predicting which patients are most at risk and developing treatments that intervene earlier.”
The research is part of Mayo Clinic’s Precure initiative, which aims to create tools that help doctors identify and stop harmful biological processes before they progress into difficult-to-treat diseases.
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Source: Mayo Clinic
