In the battle against fatty liver disease, also known as metabolic dysfunction-associated steatotic liver disease (MASLD), new research offers hope that weight-loss medications could provide an effective solution. The study, led by researchers at Yale School of Medicine and published on August 27 in Cell Metabolism, reveals crucial insights into how these drugs could combat the condition that affects nearly 40% of adults in the U.S.
MASLD arises when excess fat accumulates in the liver, leading to inflammation, fibrosis, and potentially severe complications such as permanent liver damage or cancer. Understanding how the liver processes fat is essential in developing effective treatments.
The Yale study, under the guidance of senior author Gerald Shulman, MD, Ph.D., George R. Cowgill Professor of Medicine (Endocrinology) and professor of cellular and molecular physiology, provides clarity on a long-debated issue: the rate at which the liver metabolizes fat in individuals with MASLD compared to those without the condition. The findings show that the rate of fat burning in the liver is similar across individuals with MASLD and those without it, resolving conflicting results from previous research.
A significant aspect of the study is the role of glucagon, a hormone involved in glucose metabolism. The researchers found that increasing blood levels of glucagon boosts liver metabolism in both healthy individuals and those with fatty liver disease. This discovery is noteworthy because several experimental weight-loss and diabetes drugs, such as retatrutide, include glucagon agonists. This suggests that these drugs might help manage MASLD through multiple mechanisms.
Despite existing treatments like the newly FDA-approved resmetirom, Shulman emphasizes that not all patients benefit from current therapies. “It’s evident that alternative treatments are needed,” Shulman said. He proposed that drugs enhancing mitochondrial fat oxidation in the liver could offer a promising approach.
Mitochondrial oxidation is the process by which liver cells convert fat into energy. Enhancing this process could potentially reduce fat deposits and even reverse MASLD and its more severe counterpart, metabolic dysfunction-associated steatohepatitis (MASH). The study aimed to resolve whether MASLD itself enhances mitochondrial oxidation or if increasing this process could provide therapeutic benefits.
To address this, Shulman’s team employed a novel technique called positional isotopomer NMR tracer analysis (PINTA). Unlike traditional methods that examine liver metabolism in isolated conditions, PINTA allows for the observation of metabolic reactions in their natural context. Volunteers were infused with stable isotopes to trace liver fat metabolism and measure mitochondrial oxidation and gluconeogenesis.
The analysis included 12 healthy individuals, 13 with MASLD, and 13 with MASL, a milder form of fatty liver. The results revealed comparable rates of mitochondrial oxidation across all groups, supporting some previous studies while clarifying others. Furthermore, infusing glucagon increased hepatic mitochondrial fat oxidation by 50 to 75% in both healthy and MASL groups.
Shulman noted, “This suggests that boosting glucagon levels could reduce liver fat by enhancing energy expenditure, not just by lowering energy intake.” Some weight-loss medications that improve fatty liver condition also reduce appetite, leading to decreased calorie consumption. The glucagon findings indicate that medications elevating glucagon levels might treat fatty liver by increasing energy expenditure.
Recent developments in experimental drugs combining GLP-1 agonists with glucagon-raising compounds have shown effectiveness in treating fatty liver disease. Shulman’s team plans to test these and other metabolism-related drugs further using their innovative method. They also aim to track MASLD and MASH patients over an extended period to evaluate the long-term benefits of glucagon on liver metabolism.
This study offers promising directions for improving the management of fatty liver disease, highlighting the potential of weight-loss medications to address this growing health concern effectively.
