Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis, is a serious inflammatory liver disease characterized by liver scarring or fibrosis that can lead to impaired liver function, cirrhosis, and even liver cancer. It is a significant risk factor for liver transplants in the United States. Effective treatments for MASH are limited, making it crucial to understand the underlying pathological processes driving the disease. A recent study published in PNAS explored the intricate interactions between diseased liver cells and macrophages, white blood cells that play a role in eliminating harmful cells and pathogens while promoting normal healing.
The research team, comprised of scientists from Sanford Burnham Prebys, the University of California San Diego School of Medicine, and other institutions, discovered that different macrophage subpopulations are involved in MASH progression and regression. Specifically, they identified specific macrophages that are essential for resolving MASH and liver fibrosis where scar tissue accumulation impairs liver function. When the disease regresses, lipid-associated macrophages expressing the receptor TREM2 play a crucial role in reducing inflammation and slowing down the progression of MASH-fibrosis. These findings shed light on potential therapeutic targets for treating MASH and fibrosis by leveraging the reparative functions of these macrophages.
MASH often presents without noticeable symptoms in its early and moderate stages, contributing to its widespread prevalence in the U.S. Fatty liver disease is estimated to affect 80 to 100 million Americans, with a significant portion progressing to MASH, cirrhosis, liver cancer, and related complications. The presence of TREM2-expressing macrophages is associated with a more favorable outcome in MASH regression, highlighting the importance of understanding the role of these cells in liver health and disease progression. The study also suggests a potential treatment approach involving a TREM2 agonist to stimulate the beneficial functions of these macrophages in patients undergoing other interventions like lifestyle modifications or weight loss strategies.
The authors of the study emphasize the need for expanding clinical options for MASH treatment, particularly as liver disease continues to rise in prevalence globally. With only one approved treatment for MASH currently available, exploring alternative therapeutic avenues, such as targeting macrophage subpopulations, could offer new opportunities for improving patient outcomes. The findings from this research provide valuable insights into the mechanisms underlying MASH pathogenesis and progression, pointing towards potential novel interventions that could enhance MASH and fibrosis regression. Collaboration between researchers and clinicians is essential to translate these scientific discoveries into effective clinical strategies for managing MASH and related liver diseases.
The study was supported by grants from the National Institutes of Health, Altman Clinical and Translational Research Institute, and the San Diego Digestive Diseases Research Center, among others. Researchers involved in the study, including Debanjan Dhar, David Brenner, and Christopher Glass, contributed to advancing our understanding of MASH pathophysiology and identifying potential therapeutic targets. By elucidating the roles of specific macrophage subpopulations in MASH resolution and fibrosis reduction, the study lays the groundwork for future investigations into developing targeted therapies that harness the reparative functions of these immune cells. Continued research in this field is essential for improving outcomes for individuals affected by MASH and related liver conditions, underscoring the importance of innovative approaches in managing liver disease.