Blocking the enzyme ACMSD can greatly lessen the harm caused by metabolic liver disease, according to recent research.
Metabolic dysfunction-associated steatotic liver disease (MASLD), which was previously referred to as “non-alcoholic fatty liver disease,” impacts roughly 25% of individuals worldwide. Its more serious variant, metabolic dysfunction-associated steatohepatitis (MASH), can result in liver scarring and potentially lead to liver failure. Given that there is currently only one approved treatment available, discovering effective solutions for MASLD and MASH is essential.
The development of MASLD and MASH is closely linked to obesity, unhealthy eating habits, and insufficient physical activity. These factors contribute to fat accumulating in the liver, which may lead to inflammation and scarring. Over time, this accumulation could escalate to fibrosis and cirrhosis, causing significant liver harm. Although these conditions are common, there are few treatment options for those affected by MASLD and MASH.
Another issue is the lowered amounts of NAD+ (nicotinamide adenine dinucleotide), a molecule crucial for numerous cellular functions, such as energy generation, DNA repair, and regulating inflammation. In conditions like MASLD and MASH, NAD+ levels decrease, further exacerbating liver damage and the progression of the disease. Restoring NAD+ levels could potentially halt or even reverse this damage, but how can this be achieved?
A group of researchers led by Johan Auwerx at EPFL has discovered that inhibiting an enzyme called ACMSD may provide a solution. ACMSD (α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase) is primarily present in the liver and kidneys, where it helps break down the amino acid tryptophan and regulates NAD+ production. By blocking ACMSD, the scientists found they could elevate NAD+ levels in the liver, which subsequently decreased inflammation, DNA harm, and fibrosis in mouse models of MASLD/MASH.
The researchers experimented with various models, including rodent liver cells and human liver organoids, which are miniature lab-grown livers. They also subjected mice to a high-fat Western-style diet to replicate the conditions that induce MASLD/MASH in humans. Once the disease was established in the mice, they administered an ACMSD inhibitor named TLC-065 and evaluated its effects on liver function and NAD+ levels as well as its impact on human liver organoids.
The outcomes were encouraging: By inhibiting ACMSD, NAD+ levels significantly increased, particularly in the liver, where ACMSD is vital for energy management and protection against DNA damage. This rise in NAD+ resulted in decreased inflammation, reversed fibrosis, and reduced DNA damage in the livers of the treated mice. Moreover, it was observed that ACMSD inhibition in human liver organoids lowered indicators of DNA damage.
The research suggests that targeting ACMSD could emerge as a promising new treatment for MASLD and MASH. Enhancing NAD+ production in the liver could help guard against the severe consequences of these diseases, thereby lowering the risk of progressing to cirrhosis. This strategy underscores the significance of metabolic pathways in liver disease and presents ACMSD as a new candidate for drug development.
