Fatty liver disease, now more commonly referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is rapidly becoming a major health concern in the United States, affecting nearly 40% of adults. This condition, characterized by the accumulation of excess fat in the liver, can lead to inflammation, fibrosis, and, in severe cases, permanent liver damage or liver cancer. A recent study conducted by researchers at the Yale School of Medicine (YSM) and published in the journal Cell Metabolism findings demonstrated that mitochondrial oxidation is not substantially impaired in MASL or MASLD, and glucagon can stimulate both oxidation and glucose production, highlighting its potential role in metabolic regulation for individuals with fatty liver disease.
The study assessed hepatic mitochondrial oxidation, gluconeogenesis, and β-hydroxybutyrate turnover in individuals with metabolic-dysfunction-associated steatotic liver (MASL) and metabolic-dysfunction-associated steatohepatitis (MASLD) compared to BMI-matched controls without hepatic steatosis. Using positional isotopomer NMR tracer analysis (PINTA) and magnetic resonance spectroscopy (MRS), the researchers found that hepatic mitochondrial oxidation rates were not significantly altered in individuals with MASL and MASLD compared to controls. However, a physiological increase in plasma glucagon concentrations resulted in a 50-75% increase in mitochondrial oxidation rates across both MASL and control groups. In MASL individuals, glucagon also increased glucose production by 50%, partly due to a 30% rise in mitochondrial pyruvate carboxylase activity.
This finding is particularly relevant because several experimental weight loss and diabetes medications, such as retatrutide, contain a glucagon agonist component. The results suggest that these drugs could combat fatty liver disease through multiple mechanisms.
Shulman and co-workers emphasized the need for additional therapeutic options, particularly those that can enhance the liver’s mitochondrial fat oxidation process. It has been observed that some treatments for fatty liver disease exist, such as the newly FDA-approved drug resmetirom, but these medications do not work for all patients
Mitochondrial oxidation is the process by which liver cells convert fat into energy and once researchers can find a way to increase the liver’s mitochondrial fat-burning capacity, it could reduce fat deposits in the liver and potentially reverse MASLD and the more severe form of the condition, metabolic dysfunction-associated steatohepatitis (MASH). However, it has been unclear whether these conditions increase mitochondrial oxidation on their own. Some studies suggested that fatty liver disease could already elevate the liver’s fat metabolism, raising questions about whether additional stimulation would have any impact on the disease.
The study suggests that increasing glucagon levels can have additive beneficial effects by reducing liver fat, not only by lowering energy intake but also by enhancing hepatic energy expenditure. This finding is particularly significant for patients taking weight loss medications that contain a glucagon component, such as GLP-1 agonist drugs.
Shulman and colleagues are now looking to further test the effects of these and other metabolism-related drugs on liver metabolism over extended periods. They hope to determine whether the beneficial effects of glucagon on liver metabolism persist long-term, a key factor for any successful treatment for MASLD and MASH. This research could pave the way for new, more effective therapies targeting one of the most common liver conditions in the United States.
References
- Petersen KF, Dufour S, Mehal WZ, Shulman GI. Glucagon promotes increased hepatic mitochondrial oxidation and pyruvate carboxylase flux in humans with fatty liver disease. Cell Metabolism [Internet]. 2024 Aug 27 [cited 2024 Sep 20]; Available from: https://www.sciencedirect.com/science/article/pii/S1550413124003255
- Pan CS, Stanley TL. Effect of Weight Loss Medications on Hepatic Steatosis and Steatohepatitis: A Systematic Review. Front Endocrinol (Lausanne). 2020 Feb 21;11:70.
- Beninger P. Resmetirom. Clinical Therapeutics. 2024 Jun 1;46(6):515–6.