Researchers at UT Health San Antonio are shedding new light on a little-understood biological process that could eventually influence how scientists approach metabolic diseases: the liver’s ability to release different proteins at different times of day.
The findings, highlighted Wednesday by UT Health San Antonio, show that the liver’s internal circadian clock helps determine when certain proteins are released and how those proteins interact with other tissues.
The research could eventually inform studies involving metabolism, meal timing, and the timing of medications.
The Liver May Operate on More Than One Schedule
The study, published June 2 in the peer-reviewed journal Nature Communications, examined how the liver communicates with other parts of the body through proteins released into the bloodstream.
The researchers used an experimental system to examine protein secretion from liver tissue across the daily cycle. Their analysis of male and female mice identified hundreds of proteins whose secretion varied according to the time of day or the activity of the liver’s molecular clock.
The researchers focused in particular on proteins known as hepatokines, which are proteins produced by the liver that can affect other tissues.
“Any cell with a nucleus is likely to express the molecular clock. We are interested in how cells work together and coordinate their activities,” said Kevin Koronowski, PhD, assistant professor in the Department of Biochemistry and Structural Biology at UT Health San Antonio and an investigator with the Sam and Ann Barshop Institute for Longevity and Aging Studies.
“The clock is one way the body can organize physiology in an efficient and appropriate manner,” Koronowski added.
One Protein Stood Out
One of the study’s most notable findings involved endostatin, a protein fragment produced from collagen type XVIII.
According to the researchers’ original paper in Nature Communications, the liver released more endostatin during the inactive, fasting phase of the daily cycle. Experiments conducted both in living animals and in laboratory settings found that endostatin affected the activity of mitochondria in white fat tissue and increased lipolysis, the process by which stored fat is broken down.
The researchers also found that disrupting a key component of the liver’s molecular clock altered the normal timing of endostatin production and processing. The study therefore provides evidence of a mechanism through which the liver’s clock can influence metabolic activity in another organ.
Christopher Litwin, a fourth-year PhD student in Koronowski’s laboratory and first author of the study, said researchers had already known that the liver secretes certain proteins, but lacked a sufficiently developed method for measuring when those proteins were released.
“We thought the time-dependent release of proteins may be important for coordinating metabolism in tissues like fat or muscle,” Litwin said. “The core idea is that the clock regulates protein secretion and can influence metabolism across the day, and in other tissues.”
What it Could Mean for Future Treatments
The research does not establish a new treatment for obesity, diabetes, fatty liver disease, or other metabolic conditions. Instead, it provides evidence that the timing of biological signals may be an important part of how metabolism is regulated.
That distinction is important because the study was primarily conducted using mouse liver tissue and experimental models. The Nature Communications paper identifies male and female mice as the subjects of its proteomic analysis, rather than human patients.
Still, the researchers say the findings could help guide future work on metabolic disease and the timing of treatments.
UT Health San Antonio reported that the endostatin finding suggests therapies based on the protein could potentially be more effective if delivered at an appropriate time of day, although additional research would be required before such an approach could be considered a medical treatment.
“We are interested in developing and characterizing novel peptides. We want to find the next GLP-1 drug, or even something better that is waiting to be discovered,” Koronowski said.
Why Timing Matters to Metabolism
Circadian clocks are molecular systems that help cells coordinate biological functions with the roughly 24-hour day-night cycle. Researchers have increasingly examined how disturbances in sleep, eating patterns, and other daily routines may affect metabolic processes.
The UT Health San Antonio team is examining one piece of that larger system: how the liver’s clock controls communication with other tissues.
For now, the study does not provide evidence that people should change when they eat, sleep, or take medications based on the findings. Its significance is instead in identifying a previously less-understood mechanism that researchers can investigate in future studies.
The research was supported by grants from the National Institutes of Health, the American Heart Association, and other organizations, according to the study’s authors. The researchers reported no competing interests.
