Weight-loss drugs may help fight fatty liver disease

To combat fatty liver disease, researchers are looking for every solution they can find. But to combat this disease, also known as metabolic dysfunction-associated steatotic liver disease (MASLD), scientists must first understand how the liver metabolizes fat. MASLD is on the rise in the United States, now affecting nearly 40% of adults. The disease occurs when the body deposits extra fat in the liver, leading to inflammation, fibrosis, and in some cases, permanent liver damage or liver cancer.

A new study by researchers at the Yale School of Medicine (YSM), published August 27 in the journal Cellular metabolismfound that people with MASLD burn fat in their livers at the same rate as people without the disease. The study, whose senior author is Gerald Shulman, MD, PhD, the George R. Cowgill Professor of Medicine (Endocrinology) and professor of cellular and molecular physiology at YSM, appears to settle this question, which has been controversial in the field.

The researchers also found that increasing blood levels of glucagon, a glucose-related hormone, boosts liver metabolism in both healthy people and those with fatty liver disease. This is important because some experimental weight-loss and diabetes drugs, such as retatrutide, also contain a glucagon agonist component, a welcome finding that suggests these drugs appear to combat fatty liver disease through multiple mechanisms.

Shulman points out that while there are medications available to treat fatty liver disease, including resmetirom, a drug recently approved by the FDA, these treatments don’t work for all patients.

“Clearly we need other agents,” he said, suggesting that therapies that accelerate liver mitochondrial fat oxidation might be a useful approach.

How to boost liver metabolism

Mitochondrial oxidation is the metabolic process used by liver cells to convert fat into energy. If researchers could identify a way to increase the ability of liver mitochondria to burn fat, it could reduce fat deposition in the liver and possibly even reverse steatohepatitis associated with metabolic dysfunction and liver dysfunction.

What was unclear was whether these conditions alone increased mitochondrial oxidation, because previous studies had different conclusions. If fatty liver disease already increases the organ’s fat metabolism, it seemed possible that trying to increase metabolism even more would have no effect against the disease.

To answer this question, Shulman and his team used a recently developed technique called positional isotope NMR tracer analysis, or PINTA. Many previous studies have looked at liver metabolism in cells or in test tubes in the lab because it is very difficult to follow metabolic reactions as they occur in the body. But this natural context is essential and can significantly alter metabolism compared to artificial environments, Shulman said.

In their method, study volunteers were infused with a mixture of three stable (non-radioactive) isotopes that allowed the scientists to trace the metabolism of labeled substrates (surfaces on which enzymes act) and quantify rates of liver mitochondrial oxidation and gluconeogenesis as they occur in the body.

Using this approach, they examined liver fat metabolism in 12 healthy volunteers and compared it to that of 13 study volunteers with MASLD (fatty liver disease with inflammation) and 13 volunteers with the related disease, metabolic dysfunction-associated steatotic liver, or MASL, a less severe form of fatty liver disease.

The researchers found that all three groups had similar rates of mitochondrial oxidation in their livers, which contrasts with the results of some previous studies, which confirm others. They also gave the study volunteers infusions of glucagon, a hormone that stimulates glucose production. The hormone increased liver mitochondrial fat oxidation rates in both the healthy volunteers and the MASL groups by 50 to 75 percent.

“This suggests that increasing glucagon will have additive beneficial effects in reducing liver fat, not only by reducing energy intake but also by increasing hepatic energy expenditure,” Shulman said. People who take certain weight-loss medications that also relieve fatty liver disease have reduced appetite and generally consume fewer calories, thereby reducing their overall energy intake.

The results of the glucagon study suggest that medications that increase levels of the hormone may treat fatty liver disease by increasing energy expenditure. GLP-1 agonist medications such as semaglutide (Ozempic) are known to reduce excess liver fat present in MASLD by promoting weight loss and reducing overall energy intake.

Shulman and his colleagues are looking for approaches that also increase fat metabolism. Indeed, experimental combination drugs that combine GLP-1 agonists with compounds that increase glucagon levels have recently been shown to be effective in treating fatty liver disease.

Next, Shulman and his team want to use their method to test the effects of these and other metabolism-related drugs on liver metabolism. They also want to follow study volunteers with MASLD and MASH over a longer period of time to see if glucagon’s beneficial effects on liver metabolism persist, which would be important for any successful treatment.