Scientists have uncovered how certain white blood cell subpopulations influence the progression of metabolic dysfunction-associated steatohepatitis (MASH), offering a potential pathway for new treatments.
In a landmark study published in the Proceedings of the National Academy of Sciences (PNAS), researchers have identified specific macrophage subpopulations that critically impact the progression and regression of metabolic dysfunction-associated steatohepatitis (MASH). The breakthrough offers a glimmer of hope for millions affected by this prevalent liver disease.
Formerly known as nonalcoholic steatohepatitis (NASH), MASH is an inflammatory liver disease characterized by scarring or fibrosis, progressively impairing liver function. It is a major precursor to cirrhosis and liver cancer and currently stands as the second leading cause of liver transplants in the United States, surpassed only by cirrhosis due to chronic hepatitis C infection.
The study, led by scientists from Sanford Burnham Prebys and the University of California San Diego School of Medicine, investigated the dynamic interactions between liver cells and macrophages, a type of white blood cell.
“In MASH, Kupffer cells (a type of macrophage that resides in the liver) are lost and replaced by four distinct macrophage subpopulations,” David Brenner, co-corresponding author and president and CEO of Sanford Burnham Prebys, said in a news release. “When the disease is in regression, … two lipid associated macrophage subpopulations are dominant and express TREM2, a cell receptor that regulates cell survival, proliferation and anti-inflammatory responses.”
Senior author Debanjan Dhar, an associate professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys, emphasized the significance of these findings.
“Our findings suggest that lipid-associated macrophages that express TREM2 and TREM2 are required both for the emergence of more liquid associated macrophages and for their reparative functions,” he said in the news release.
This implies that the presence of TREM2+ macrophages is instrumental in restricting and even reversing the progression of MASH and fibrosis.
The discovery could pave the way for new therapeutic approaches. The researchers speculate that a TREM2 agonist, a drug that mimics TREM2 functions, might become a valuable asset in treating MASH/fibrosis, especially when combined with lifestyle changes.
“There is only one approved treatment for MASH, and it was only approved earlier this year,” added co-corresponding author Christopher Glass, a professor of cellular and molecular medicine at UC San Diego. “Any opportunities to expand clinical options that benefit patients need to be thoroughly pursued because liver disease in this country — and around the world — is only getting worse.”
MASH often goes undetected due to a lack of early symptoms, contributing to its widespread prevalence. According to the American Liver Foundation, an estimated 80 to 100 million Americans have fatty liver disease, with a significant portion progressing to MASH, cirrhosis or liver cancer if left untreated.
As liver disease continues to escalate globally, the insights from this study could mark an essential step toward developing effective treatments to improve patient outcomes and quality of life.