Metabolic dysfunction-associated steatohepatitis (MASH) is on the rise around the globe, threatening to become the country’s leading cause of liver transplantation by 2025.
Affecting 5% of adults nationwide, MASH is a subtype of nonalcoholic fatty liver disease—a spectrum of conditions marked by a buildup of fat in the liver unrelated to alcohol use. In the United States alone, where two in five adults have obesity, according to the Centers for Disease Control and Prevention (CDC), the number of cases is projected to hit 27 million in 2030.
Until recently, the only treatment options were diet and lifestyle changes. Even the first drug for MASH approved by the Food and Drug Administration, Resmetirom (Rezdiffra), just targets one aspect of the disease by activating a thyroid hormone receptor that reduces liver fat accumulation.
However, research led by Vassilios Papadopoulos, dean of the USC Mann School of Pharmacy and Pharmaceutical Sciences, represents a potential breakthrough in stopping MASH by shutting down multiple pathways of progression, so the liver can heal and regenerate.
The research, first published online in Metabolism on June 11, 2024, describes the laboratory testing of this possible first-in-class therapy and its unique mechanism of action. Rats fed a fatty diet reflective of what causes MASH in humans were treated with Atriol, a protein important to binding cholesterol. Previous work by Papadopoulos and colleagues demonstrated that Atriol may be effective against MASH. The current study bears out that hypothesis, as Atriol significantly eased the disease in the rats treated.
The Atriol therapy reduced the size of their livers relative to their body weight, lowered their blood cholesterol and fat levels, and decreased liver scarring and inflammation. The likely reason for these improvements is that Atriol reduces the activity of a protein called TSPO, which is found in mitochondria—the energy-producing parts of cells.
“These in vivo studies revealed that Atriol treatment effectively mitigated MASH,” Papadopoulos says.
The USC scientists’ discovery comes at a time when there are several types of MASH medications in late-stage clinical trials, and a surge in GLP-1-based weight-loss drugs that have been shown to reduce weight, improve metabolic health and remove liver fat.
“Our study suggests that Atriol is a promising therapeutic candidate with multiple benefits, effectively reducing liver steatosis, fibrosis, inflammation and cell death and restoring mitochondrial function in MASH,” Papadopoulos says.
In addition to Papadopoulos, the paper’s other authors are Yuchang Li, Liting Chen, Chantal Sottas, Mahima Chandrakant Raul, Nrupa Dinesh Patel, Janaki Ramulu Bijja, S. Kaleem Ahmed, Alexander Zambidis, Shefali Chopra, Meng Li, Go Sugahara and Takeshi Saito of USC; Audrey Kapelanski-Lamoureux, Anthoula Lazaris and Peter Metrakos of the Research Institute of McGill University Health Center in Montreal.
The work was supported by funds from the USC Mann School and the John Stauffer Dean’s Chair in Pharmaceutical Sciences at USC.