Previously known as nonalcoholic steatohepatitis, metabolic dysfunction-associated steatohepatitis (MASH) is an inflammatory disease characterized by scarring or fibrosis of the liver that progressively deteriorates 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 transplants in the United States after cirrhosis caused by chronic hepatitis C infection.
A better understanding of the pathological processes that drive MASH is critical to creating effective treatments. In a new paper published August 19, 2024 in PNAS, A team of scientists from Sanford Burnham Prebys, the University of California San Diego School of Medicine and elsewhere describes the complex interplay between diseased liver cells and macrophages, a type of white blood cell whose functions include killing and removing harmful cells and pathogens and helping to stimulate normal healing.
The senior author of the study is Dr. Debanjan Dhar, associate professor in the Cancer Genome and Epigenetics Program at Sanford Burnham Prebys. Dr. David Brenner, president and CEO of Sanford Burnham Prebys, and Dr. Christopher Glass, professor of cellular and molecular medicine at UC San Diego, are the corresponding authors. Dr. Souradipta Ganguly, 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 was different, depending on whether the disease was progressing or receding. More importantly, they identified specific subpopulations of macrophages that are critical to resolving MASH and liver fibrosis in which the buildup 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 macrophage subpopulations. When the disease is in regression (i.e., symptoms or severity are decreasing), 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. These not only restrict the progression of fibrosis by MASH, but effectively slow it down and reduce inflammation. The absence of TREM2+ macrophages allows the disease to progress.”
In early and moderate stages, MASH often produces no telltale symptoms, which is part of the reason it has reached epidemic proportions in the U.S. The American Liver Foundation estimates that 80 to 100 million Americans have fatty liver disease that, undiagnosed and untreated, progresses to nonalcoholic steatohepatitis, MASH, cirrhosis, liver cancer, and death, often in combination with other conditions, such as obesity.
It is estimated that between 1.5% and 6.5% of American adults have MASH, and approximately 24% of adults have steatotic fatty liver disease associated with metabolic dysfunction, the starting point for MASH, cirrhosis, and worsening disease.
“Our findings suggest that lipid-associated macrophages expressing TREM2 and TREM2 are required for both the emergence of more fluid-associated macrophages and their reparative functions,” Dhar said.
“Effective scar tissue degradation as a protective mechanism is mediated by TREM2, and the absence of TREM2+ macrophages not only impairs the liver’s ability to clear fibrotic tissue, but also impairs the entire immune response and healing process.”
In the future, the 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 who are also undergoing lifestyle modifications, weight loss, or bariatric surgery.
“There is only one approved treatment for MASH, and it was approved earlier this year,” Glass said. “Any opportunity to expand clinical options that benefit patients needs to be maximized, because liver disease in this country — and around the world — is 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, of Janssen Research & Development, San Diego.
This study was supported by grants from the National Institutes of Health to DD (R01DK137061, R01DK133930), Altman Clinical and Translational Research Institute (ACTRI — KL2TR001444), and the San Diego Digestive Disease Research Center (NIH DK120515). It was partially funded by ACTRI (NIH UL1TR001442). TK was supported by NIH grants DK099205, AA028550, DK101737, AA011999, DK120515, AA029019, DK091183; CKG by NIH grants DK091183 and HL147835. TDT was supported by NIH grants P30DK063491, T32DK007044, and P30DK078392, the American Association for the Study of Liver Diseases (PNC23-216751), and the Center for Inflammation and Tolerance through the Cincinnati Children’s Research Foundation. RL received financial support from NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515), NHLBI (P01HL147835), and the John C. Martin Foundation (RP124). JMO was supported by the Diabetes Research Center (P30DK063491) and the Horton JPI MRA: Obesity and its metabolic complications (20175015). AEF was supported by NIH grant R01DK113592. TVR was supported by grants from the Swiss National Science Foundation (P2BSP3_200177) and the Larry L. Hillblom Foundation (2023-D-012-FEL).