Gerald Shulman, MD, PhD, is very concerned about the state of Americans’ liver health.
Fatty liver disease, also known as metabolic dysfunction-associated steatotic liver disease, or MASLD, affects nearly 40% of U.S. adults and its prevalence is rising fast.
“Fatty liver disease is becoming as important a problem as type 2 diabetes in some ways,” said Shulman, George R. Cowgill Professor of Medicine (Endocrinology) and professor of cellular and molecular physiology at Yale School of Medicine (YSM).
MASLD, which is characterized by excess fat deposits in the liver, is associated with type 2 diabetes and obesity and can itself raise the risk of diabetes and heart disease. But the good news is that fatty liver disease can often be reversed, either through lifestyle changes or medications that reduce the liver’s extra fat.
Shulman and his laboratory team at YSM are interested in understanding the details of how the liver burns fat with the ultimate goal of developing new ways to increase the organ’s fat metabolism and treat MASLD, formerly known as nonalcoholic fatty liver disease (NAFLD). The exact cause of this disease isn’t known but the excess fat can eventually lead to inflammation and liver scarring, or cirrhosis, the same kind of damage that can be caused by excessive alcohol consumption.
In a new study led by Shulman that was published August 16 in the journal Cell Metabolism, the team describes a surprising finding about how mice metabolize fat in their livers: It turns out that this metabolism relies on a different mineral source than had previously been widely accepted in the field.
Liver fat metabolism happens in specialized subcellular compartments known as mitochondria, organelles that also generate all of our cells’ energy. The chemical reactions that turn fat into energy rely on the dietary mineral calcium, and it had long been thought that calcium located inside the mitochondria themselves was the key regulator of these reactions. The Yale study concluded that a different source of calcium in the cell is actually what’s important for the liver fat metabolism, and it further identified a protein that regulates this process.
A hypothesis upended
To understand whether mitochondrial calcium regulates energy production, the researchers turned to a line of mice genetically engineered to lack a certain protein in their liver cells. That protein, called the mitochondrial calcium uniporter or MCU, transports calcium from the rest of the cell into the mitochondria. Mice lacking MCU in their livers indeed have lower levels of calcium in their liver mitochondria, but the team found that, contrary to their expectation, the animals actually had higher rates of mitochondrial metabolism and reduced levels of fat in their livers.
It's a basic science question that is giving us insights into this critical process that could be amenable to treating fatty liver disease as well as type 2 diabetes.
Gerald Shulman, MD, PhD
Upon further exploration, Shulman and his colleagues found that calcium in the cytosol, the fluid that fills up cells, appears to drive mitochondrial metabolism. With this finding, it’s now unclear what role calcium plays in the mitochondria, although it’s possible that different tissues in the body may handle their metabolism differently, Shulman said. The researchers also found a specific protein, CAMKII, that appears to regulate this cytosolic calcium-based metabolism.
To uncover these results, the Yale team used a novel technique they had previously developed, called Q-Flux, that captures the flow of molecules into and out of mitochondria in the liver. This technique allowed them to study the rates of metabolic reactions happening in mitochondria in living animals. Most previous studies of mitochondrial metabolism were performed in test tubes in the lab, outside these organelles’ natural context.
“Often what you’re measuring in the mitochondria can be impacted by whatever artificial substrates or conditions you have in the test tube,” Shulman said. “We’re able to measure things under the conditions that liver cells normally experience in vivo.”
The results point to new avenues that could ultimately lead to better drug development for MASLD, Shulman said. There are two mechanisms to reduce fat deposits in the liver: decrease the amount of fat that’s deposited there in the first place or increase liver metabolism to burn more fat. GLP-1 agonist drugs, such as semaglutide (Ozempic), work via the first mechanism to reverse fatty liver disease, but Shulman is interested in finding ways to accomplish the second mechanism as a complement to the first one. The protein they identified as being involved in the process, CAMKII, could be a potential drug target, he said; however, that protein is also involved in glucose production and so interfering with its activity could have other consequences in the body.
“It's a basic science question that is giving us insights into this critical process that could be amenable to treating fatty liver disease as well as type 2 diabetes,” Shulman said.