Study Finds Macrophage Mix Helps Determine Rate and Progression of Hepatic Steatosis

Formerly known as nonalcoholic steatohepatitis, metabolic dysfunction-associated steatohepatitis (MASH) is an inflammatory disease characterized by scarring or fibrosis of the liver that progressively impairs liver function.

It is a major risk factor for cirrhosis and liver cancer. And because treatment options are limited, MASH is the second leading cause of liver transplantation in the United States after cirrhosis caused by chronic hepatitis C infection.

A better understanding of the pathological processes underlying MASH syndrome is essential to creating effective treatments. In a new paper published in Proceedings of the National Academy of Sciences, A team of scientists from Sanford Burnham Prebys, the University of California San Diego School of Medicine and elsewhere describes the complex interaction between diseased liver cells and macrophages, a type of white blood cell whose jobs include killing and removing harmful cells and pathogens and promoting normal healing.

Debanjan Dhar, Ph.D., associate professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys, is the study’s senior author. David Brenner, MD, president and CEO of Sanford Burnham Prebys, and Christopher Glass, MD, Ph.D., professor of cellular and molecular medicine at UC San Diego, are the corresponding authors. Souradipta Ganguly, Ph.D., a postdoctoral researcher at UC San Diego and Sanford Burnham Prebys, is the first author.

The researchers found that the heterogeneous mix of macrophages involved in MASH differed depending on whether the disease was progressing or regressing. More importantly, they identified specific subpopulations of macrophages that are critical to resolving MASH and liver fibrosis in which the accumulation of scar tissue impairs the organ’s ability to function or repair itself. These fibrotic bands restrict blood flow, putting the entire organ at risk.

“In MASH, Kupffer cells (a type of macrophage that resides in the liver) are lost and replaced by four distinct subpopulations of macrophages. When the disease is in regression, meaning symptoms or severity decrease, two lipid-associated macrophage subpopulations are dominant and express TREM2, a cellular receptor that regulates cell survival, proliferation and anti-inflammatory responses,” Brenner said.

“MASH regression occurs in the presence of TREM2+ macrophages. Not only do they limit the progression of MASH fibrosis, they effectively slow it down and reduce inflammation. The absence of TREM2+ macrophages allows the disease to progress.”

In its early and moderate stages, MASH often produces no telltale symptoms, which is one reason why it has reached epidemic proportions in the United States. The American Liver Foundation estimates that 80 to 100 million Americans have fatty liver disease, which, if undiagnosed and untreated, progresses to nonalcoholic steatohepatitis, MASH, cirrhosis, liver cancer, and death, often in association with other diseases, such as obesity.

It is estimated that between 1.5% and 6.5% of American adults have or are affected by MASH, and approximately 24% of adults have steatotic liver disease associated with metabolic dysfunction, the starting point for MASH, cirrhosis, and worse.

“Our results suggest that lipid-associated macrophages that express TREM2 and TREM2 are required for both the emergence of more fluid-associated macrophages and their reparative functions,” Dhar said. “The efficient degradation of scar tissue as a protective mechanism is mediated by TREM2, and the absence of TREM2+ macrophages not only disrupts the liver’s ability to clear fibrous tissue, but also impairs the entire immune response and healing process.”

In the future, scientists say a TREM2 agonist (a drug or substance that mimics the function of TREM2) could be beneficial for MASH/fibrosis therapy and help stimulate regression of MASH and fibrosis in patients also undergoing lifestyle modification, weight loss, or bariatric surgery.

“There is only one approved treatment for MASH, and it was only approved earlier this year,” Glass said. “Any opportunity to expand clinical options that benefit patients needs to be explored carefully, because liver disease in this country – and around the world – is only getting worse.”

Other authors of the study are Sara Brin Rosenthal, Kei Ishizuka, Theresa V. Rohm, Naser Khader, Sebastiano Archilei, Jerrold M. Olefsky, Ariel E. Feldstein, Tatiana Kisseleva and Rohit Loomba, all of UC San Diego; Ty D. Troutman, of UC San Diego and Cincinnati Children’s Hospital Medical Center, and German Aleman Muench, Yasuyo Sano and Pejman Soroosh, Janssen Research & Development, San Diego.