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Restoring the enzyme UBE2N reduced fatty liver damage in mice
Cedars-Sinai-led researchers found that restoring the enzyme UBE2N reduced fat buildup, inflammation and scarring in mouse livers. The Nature Metabolism study offers a drug target for slowing fatty liver disease, backed so far only by mouse data.
The Scientist · Science desk
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What happened
- UBE2N levels in liver cells fell as the disease grew more advanced, the multicenter study found.
- Earlier research had suggested that damaged mitochondria, the cell's energy producers, may contribute to MASH developing and progressing.
- An estimated 20 to 25% of the roughly 100 million Americans with MASLD go on to develop MASH, the form in which excess fat comes with inflammation, cell injury and scarring.
- MASH has no cure, and care centers mainly on lifestyle changes and on limiting further liver damage, with few drug options available.
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Why it matters
- constraint The evidence that losing UBE2N causes damage comes from one intervention in one species, so the case for it as a human target depends on human tissue data and trials that have not yet been reported.
- decision A UBE2N drug program would have to boost an enzyme pathway in the liver. Lu names that enhancement, along with choosing which patients benefit, as the tests still ahead.
- capability If the mouse result carries over to people, developers would have a target aimed at mitochondrial clearance and fat breakdown, in a disease now managed largely through lifestyle change.
The study offers two kinds of evidence, and they do different jobs. The falling enzyme levels are an observation [4]. On their own, they fit a story in which UBE2N protects the liver. They fit just as well a story in which the enzyme is one more casualty of a liver already under strain.
The mouse experiment is the test that separates those readings. The team restored UBE2N to normal levels in the livers of laboratory mice and recorded reductions in fat accumulation, inflammation and scarring [5]. Putting back a bystander molecule should not change the outcome. In these mice it did, and I think that intervention is the strongest result in the preclinical work as Cedars-Sinai has described it [1].
Ekihiro Seki, a professor of medicine and biomedical sciences at Cedars-Sinai and a co-corresponding author [12], tied the protection to two jobs inside liver cells. "The UBE2N enzyme appears to protect the liver from the inflammation and damage associated with MASH by helping remove damaged mitochondria and supporting the breakdown of fat," Seki said [6]. "When levels of the enzyme fell, we saw more damaged cells and injury to the liver," he said [8].
The press release does not report how many mice were used, how the enzyme was restored or how large the reductions were. It also does not say whether the drop in UBE2N was measured in human liver tissue as well as in animals [5].
The thing this does not tell you is whether restoring the enzyme would help a liver that has already progressed. The researchers frame UBE2N as a potential target for preventing MASLD from advancing to MASH [10]. Applied to the American Liver Foundation estimates, that progression rate works out to 20 to 25 million Americans who go on to develop MASH [1].
Shelly Lu, director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai [13], called the finding "an important advance in understanding steatotic liver disease" [14] and set out what still has to be tested. "Future studies can test whether enhancing this protective pathway can complement existing treatments, identify patients most likely to benefit and lead to new therapeutic approaches for preventing advanced disease," Lu said [11].
What to watch
- Whether the full Nature Metabolism paper shows the UBE2N decline in human liver biopsies as well as in mouse livers.
- The size of the reductions in fat, inflammation and scarring, and the method the team used to restore UBE2N in mice.
- Studies testing whether enhancing UBE2N adds benefit on top of existing MASH treatments, as Lu proposed.