Today, metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent condition that affects approximately 25% of the global population. Formerly known as “non-alcoholic fatty liver disease,” MASLD can progress to its severe form, metabolic dysfunction-associated steatohepatitis (MASH), which can lead to liver fibrosis and ultimately, liver failure. Unfortunately, there is only one approved treatment available for MASLD and MASH at the moment, making the search for new solutions imperative.
MASLD and MASH are closely linked to lifestyle factors such as obesity, poor diet, and lack of exercise. These factors contribute to fat accumulation in the liver, leading to inflammation and scarring. Over time, this can advance to fibrosis and cirrhosis, causing significant liver damage. Despite the high prevalence of these conditions, there are limited treatment options available for individuals suffering from MASLD and MASH.
One of the key issues in MASLD/MASH is the decreased levels of a molecule called NAD+ (nicotinamide adenine dinucleotide), which is essential for various cellular processes, including energy production, DNA repair, and inflammation control. In individuals with MASLD/MASH, NAD+ levels decrease, exacerbating liver damage and disease progression. Restoring NAD+ levels could potentially halt or even reverse this damage, but the question remains – how?
A breakthrough study led by scientists at EPFL, headed by Johan Auwerx, has shed light on a potential answer. The researchers discovered that inhibiting an enzyme called ACMSD could be a promising strategy. ACMSD (α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase) is primarily found in the liver and kidneys and is involved in breaking down the amino acid tryptophan, thereby limiting NAD+ production. By blocking ACMSD, the researchers observed a significant increase in NAD+ levels in the liver, which subsequently reduced inflammation, DNA damage, and fibrosis in mouse models of MASLD/MASH.
The researchers employed various models, including rodent liver cells and human liver organoids, to mimic the conditions that lead to MASLD/MASH. Mice were fed a Western-style diet high in fat to induce the development of the disease, after which they were administered an ACMSD inhibitor called TLC-065. The effects of the inhibitor on liver function and NAD+ levels in the mice, as well as on human liver organoids, were then evaluated.
The results were highly promising: Inhibiting ACMSD led to a significant increase in NAD+ levels, particularly in the liver, where ACMSD plays a crucial role in energy metabolism and DNA protection. This elevation in NAD+ levels resulted in reduced inflammation, reversed fibrosis, and DNA damage in the livers of the treated mice. Additionally, inhibiting ACMSD in human liver organoids also showed a reduction in markers of DNA damage.
These findings suggest that targeting ACMSD could be a novel therapeutic approach for MASLD and MASH. By enhancing NAD+ production in the liver, this strategy may offer protection against the severe damage caused by these diseases and decrease the risk of progression to cirrhosis. Furthermore, this study underscores the significance of metabolic pathways in liver disease and presents ACMSD as a promising target for future drug development efforts.
In conclusion, the research conducted by Johan Auwerx and his team at EPFL offers hope for individuals suffering from MASLD and MASH. By uncovering the potential benefits of inhibiting ACMSD to boost NAD+ levels and alleviate liver damage, this study paves the way for new therapeutic strategies in the treatment of these challenging conditions. The findings highlight the importance of targeting metabolic pathways in liver disease and present a promising avenue for future research and drug development initiatives.
