Alcohol consumption disrupts protein that controls liver fat: Study
Results suggest potential target for liver disease treatment
Exposure to excessive alcohol disrupts the activity of a protein that plays a key role in keeping liver fat healthy, a study found. Researchers said the results suggest that targeting it and related proteins may be a viable strategy for treating fatty liver disease.
The study sheds new light on the biological mechanisms by which alcohol consumption can lead to a dangerous buildup of fat in the liver.
The scientists found that valosin-containing protein (VCP) is important for regulating levels of the liquid droplets that store liver fat.
“This study increases our understanding of the biology of lipid droplets, the central culprit of fatty liver, and how the [liver cell] works in an effort to reduce its fat content,” Mark McNiven, PhD, the study’s senior author and a researcher at the Mayo Clinic, said in a clinic news story. “It also could help predict which patients are prone to the detrimental effect of excessive alcohol consumption on their liver if this cellular system is compromised.”
The study, “An ethanol-induced loss of the lipid droplet–associated segregase VCP/p97 leads to hepatic steatosis,” was published in the Journal of Cell Biology.
‘Astounding’ results tie alcohol to fat-regulating mechanisms
Alcohol-associated liver disease (ALD) and metabolic dysfunction-associated fatty liver disease (MASLD) are the two main forms of fatty liver disease. Both are marked by excessive fat in the liver, though the underlying disease causes are different: ALD is driven by alcohol consumption, whereas MASLD typically occurs in association with underlying metabolic conditions like obesity or diabetes.
Liver fat is stored mainly in lipid droplets, cellular structures composed of neutral fatty molecules and involved in fat storage and metabolism. In ALD and MASLD, these droplets accumulate to excessive levels, which can lead to inflammation that damages the liver.
That means “understanding the mechanisms that regulate [liver lipid droplet balance] is crucial for developing better management strategies for ALD and MASLD,” two researchers at the University of Kansas Medical Center who were not involved in the study, wrote in an editorial published alongside the study.
Through a series of tests in lab models, the Mayo team found that VCP (also known as p97) plays a key role in regulating levels of lipid droplets.
The researchers first found that livers from alcohol-fed rats showed reduced VCP levels and increased levels of another protein called hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) at the surface of lipid droplets.
VCP was found to be responsible for transporting HSD17B13 from the surface of lipid droplets to lysosomes, the cell’s waste disposal system, where HSD17B13 is broken down.
“It was astounding to see this,” Sandhya Sen, PhD, the study’s lead author at Mayo Clinic. “We tried several experiments to confirm what we were seeing, and every result indicated VCP directs the [HSD17B13] protein from the lipid droplet to the lysosome.”
Further experiments showed that HSD17B13’s removal from lipid droplets helps to prevent their accumulation. The team found that either suppressing VCP or increasing HSD17B13 levels in lab-grown liver cells increased lipid droplets.
Mice lacking VCP in their livers developed fatty liver disease even when fed a standard chow diet designed not to cause health problems.
“When [HSD17B13] accumulates, the fat content in liver cells balloons and contributes to fatty liver disease,” McNiven said.
The researchers found that exposure to alcohol removes VCP from the surface of lipid droplets, so it can no longer remove HSD17B13 and prevent abnormal lipid droplet accumulation.
“These findings provide new insights into the cellular mechanisms by which the liver regulates its lipid [fat] stores and how this is disrupted by chronic [alcohol] exposure,” they wrote.
The Kansas scientists wrote in their editorial that “targeting this [VCP-HSD17B13] pathway may significantly impact treating ALD and MASLD.”
The Mayo Clinic researchers noted that more work will be needed to figure out the biochemical details of exactly how alcohol causes VCP to come off of lipid droplets.
The research was part of Mayo Clinic’s Precure initiative, which aims to develop tools to allow clinicians to predict and intervene in biological processes before they turn into disease or become hard-to-treat conditions.
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