Could a New Discovery Help Beat Fatty Liver Disease?

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Image credit: https://openai.com/index/dall-e/  


Fatty liver disease, or metabolicdysfunction-associated steatotic liver disease (MASLD), is becoming a widespread health problem, affecting up to 25% of people worldwide. A more severe form, called metabolic dysfunction-associated steatohepatitis (MASH), can lead to serious liver damage like cirrhosis. But there's some good news: scientists are exploring new ways to tackle these conditions, and one recent study has revealed a promising approach.


What's the big idea? The study, published in the Journal of Hepatology, looks at a special enzyme called ACMSD, which is mainly found in the liver and kidneys. Enzymes are like tiny workers in our bodies that speed up chemical reactions. ACMSD plays a role in how our bodies produce a vital substance called NAD+.

NAD+ is like a rechargeable battery for our cells. It's involved in many important processes, including energy production and repairing damaged DNA. Previous research has shown that boosting NAD+ levels can have impressive health benefits, particularly for fatty liver disease.

The researchers in this study wanted to see if inhibiting ACMSD could be a useful strategy for treating MASLD/MASH. In other words, they wanted to slow down the enzyme to see if it would improve liver health.


How did they do it? The scientists used a multi-pronged approach:

  • Lab experiments: They conducted experiments using rodent liver cells, human liver cancer cells, and 3D models of human livers called organoids.
  • Mouse studies: They fed mice a high-fat, Western-style diet to mimic MASLD/MASH. Some of these mice were also given a special compound called TLC-065, which inhibits ACMSD.
  • Analyzing human data: The team looked at genetic information and liver samples from people with MASLD/MASH to see if there were any links between DNA damage, NAD+ and the disease.


What did they find? The results were quite encouraging:

  • Increased NAD+: Inhibiting ACMSD increased NAD+ levels in liver cells and organoids.
  • Reduced DNA damage: The researchers observed less DNA damage in liver cells when ACMSD was inhibited.
  • Improved liver health in mice: In the mice fed a high-fat diet, inhibiting ACMSD reduced liver inflammation and scarring (fibrosis).
  • Benefits in human liver models: The positive effects of ACMSD inhibition were also seen in human liver organoid models of steatohepatitis.
  • Genetic link: Analyzing human data suggested that DNA damage may play a causal role in MASLD/MASH.


Why is this important? These findings suggest that ACMSD could be a promising target for new treatments for MASLD/MASH. By inhibiting this enzyme, it might be possible to:

  • Boost NAD+ levels in the liver: This could improve cellular function and energy production.
  • Protect DNA from damage: This could prevent further liver damage and reduce the risk of complications.
  • Reduce inflammation and fibrosis: This could slow down the progression of the disease.


What's next? While these results are exciting, it's important to remember that this is still early research. More studies are needed to:

  • Confirm these findings in humans: Clinical trials will be necessary to see if ACMSD inhibitors are safe and effective for people with MASLD/MASH.
  • Understand the long-term effects: Researchers need to investigate the long-term effects of ACMSD inhibition on liver health and overall well-being.
  • Develop specific ACMSD inhibitors: The compound used in this study, TLC-065, is a research tool. Scientists need to develop drugs that are specifically designed to target ACMSD in humans.


The bottom line: This study offers a glimmer of hope for people with MASLD/MASH. By targeting ACMSD and boosting NAD+ levels, it may be possible to protect the liver from damage and slow down the progression of this increasingly common disease. While more research is needed, this discovery could pave the way for new and effective treatments in the future.

 

Additional information: ACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASH. Journal of Hepatology (2025). https://doi.org/10.1016/j.jhep.2024.08.009

Journal information: https://www.journal-of-hepatology.eu/

Location: Oxford, UK

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