Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly referred to as “non-alcoholic fatty liver disease,” impacts roughly 25% of the world’s population. Its more serious variant, metabolic dysfunction-associated steatohepatitis (MASH), has the potential to progress to liver fibrosis and, in severe cases, liver failure. Currently, there is only one approved treatment, making the pursuit of effective solutions for MASLD and MASH imperative.
Both MASLD and MASH are intricately linked to obesity, unhealthy dietary habits, and insufficient physical activity. These factors lead to the buildup of fat in the liver, resulting in inflammation and scarring. If left unchecked, these issues can advance to fibrosis and cirrhosis, causing considerable liver harm. Despite their widespread occurrence, treatment options for individuals affected by MASLD and MASH remain sparse.
Another challenge arises from the diminished levels of a molecule known as NAD+ (nicotinamide adenine dinucleotide), which is essential for numerous cellular functions, such as energy production, DNA repair, and the regulation of inflammation. In cases of MASLD/MASH, NAD+ levels decrease, contributing to liver damage and the advancement of the disease. Restoring these NAD+ levels might halt or even reverse this damage—raising the question of how this can be achieved.
A research team led by Johan Auwerx at EPFL has demonstrated that inhibiting an enzyme named ACMSD could offer a solution. ACMSD (α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase) is predominantly located in the liver and kidneys and is involved in the breakdown of the amino acid tryptophan while also regulating NAD+ production. By inhibiting ACMSD, the researchers were able to elevate NAD+ levels in the liver, which subsequently decreased inflammation, DNA damage, and fibrosis in mouse models of MASLD/MASH.
The scientists utilized various models, including rodent liver cells and lab-grown human liver organoids. They induced a Western-style high-fat diet in mice to replicate the conditions leading to MASLD/MASH in humans. After the disease had developed in these mice, they administered an ACMSD inhibitor called TLC-065 and monitored its impact on liver function and NAD+ levels, as well as its effects on human liver organoids.
The results were encouraging: Inhibition of ACMSD substantially elevated NAD+ levels particularly in the liver, where ACMSD plays a vital role in energy metabolism and helps safeguard against DNA damage. This increase in NAD+ led to reduced inflammation and reversed fibrosis and DNA damage in the livers of treated mice. Furthermore, inhibiting ACMSD in human liver organoids also decreased indicators of DNA damage.
These findings suggest that targeting ACMSD could represent a promising new treatment for MASLD and MASH. By increasing NAD+ production in the liver, this approach may help protect against the significant damage caused by these ailments, thereby lowering the risk of progression to cirrhosis. Additionally, this research underscores the critical role of metabolic pathways in liver disease and points to ACMSD as a novel target for drug development.