Blocking circulating protein interferon-γ pathway could lead to potential treatment for metabolic liver disease

University of Massachusetts Medical School researchers have identified a novel pathway in the progression of metabolic liver disease that could be targeted for potential therapies. Their findings describe how the circulating protein interferon-γ, which is higher in people with obesity, causes inflammation. By blocking this pathway, they were able to protect animal models from developing metabolic dysfunction-associated steatohepatitis (MASH).

Image 1: Lyz-IFNγR2−/− mice are rescued from fatty liver progression to MASH (Credit: Nature Communications (2024). DOI: 10.1038/s41467-024-49633-y)

"The liver can normally store some fat, but something about that process is where inflammation develops," said Dr Jason Kim, professor of molecular medicine and medicine. "That's what leads to this pathogenic disease progression. We think that we found a way to stop that from happening."

MASH, the more severe form of metabolic liver disease, is characterised by inflammation, insulin resistance and liver scarring (fibrosis). Thirty percent of people over age 60 and three out of four of people with obesity have metabolic liver disease, signifying a pressing global health issue. Despite its prevalence, only one drug has recently been approved by the FDA for treating it.

"Normally, people with MASH would be counselled to change diet and exercise. However, this discovery would help us prevent the disease from progressing without needing patients to make major lifestyle changes," Kim added.

He explained that it has long been known that inflammation develops during metabolic liver disease, but how this inflammation occurs and how it affects the liver cells have not been understood.

Image 2: Proposed model of the IFNγ-IL12 axis regulating liver insulin resistance and MASH (Credit: Nature Communications (2024). DOI: 10.1038/s41467-024-49633-y)

Using novel transgenic mice, the research team showed that blocking these macrophages or immune cells and their communication with liver cells reduces inflammation and the progression of metabolic liver disease in obesity, a first according to Kim.

The next step is to identify the nature of the crosstalk between liver macrophages and hepatocytes or liver cells and how this communication can be modified to stop the progression of metabolic liver disease.

"Understanding the role of inflammation in the liver and identifying molecular targets to block this process will lead to new therapies to treat the epidemic population," concluded Kim.

The findings were featured in the paper, ‘IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease’, published in Nature Communications’. To access this paper, please click here