Researchers at The University of Texas at San Antonio (UT San Antonio) have uncovered a treasure trove of information about hundreds of proteins released by the liver and how the timing of their release may affect bodily processes.
A recent study, published June 2 in Nature Communications, describes how the liver releases certain proteins at different times and how those proteins communicate with other organs. Findings from this study could provide the groundwork for future research into the importance of meal timing and the timing of medications.
For many biological functions, timing is everything. Kevin Koronowski, PhD, assistant professor in the Department of Biochemistry and Structural Biology at the Joe R. and Teresa Lozano Long School of Medicine and the Sam and Ann Barshop Institute for Longevity and Aging Studies, said there are potentially as many “internal clocks” as there are cells in the body, all working in concert with each other.
“Any cell with a nucleus is likely to express the molecular clock. We are interested in how cells work together and coordinate their activities. The clock is one way the body can organize physiology in an efficient and appropriate manner,” Koronowski said.
For decades, physicians have observed that disruptions to sleep schedules and irregular eating habits can lead to higher rates of obesity, diabetes and other metabolic disorders.
The liver is especially sensitive to changes in eating patterns. Just as the body operates on a circadian rhythm, the liver itself has its own internal clock.
Christopher Litwin, a fourth-year PhD student in Koronowski’s lab and first author on the study, said while it was known that the liver regulates the secretion of some of these proteins, they lacked a developed measure of how and when proteins were released.
“We thought the time-dependent release of proteins may be important for coordinating metabolism in tissues like fat or muscle. The core idea is that the clock regulates protein secretion and can influence metabolism across the day, and in other tissues,” Litwin said.
Not all liver-secreted proteins were time-dependent, but the ones that are appear to be on a strict schedule, released during active periods or periods of rest.
Extracellular matrix proteins, which make up the basement membrane, a structural support within which cells or organs sit, are released during rest periods. One of these proteins, a collagen fragment called endostatin, emerged as a key influencer in metabolism.
Koronowski explained that the liver does not just simply process nutrients — it actively communicates with other organs, including fat tissue, by releasing signaling molecules at specific times of the day and night.
“This study shows [in animal models] that endostatin has a much more pronounced effect on breaking down fat stores at the time of day it is normally secreted from the liver,” he said.
The Koronowski lab’s broader interests include chronotherapy — the method of administering medical or behavioral interventions in alignment with the body’s natural circadian cycle for maximum benefit.
“If endostatin, for example, was translated into the clinical setting and given as a drug during an active phase [instead of rest phase], there is a good chance it would not have the maximum therapeutic benefit. Considering the time of day could be important for translating treatments more broadly,” Koronowski said.
The findings suggest that while what we eat and the treatments we take are important, just as important may be when metabolic signals are sent and received throughout the body.
This study focused on liver-secreted proteins released under normal conditions, but future research will also focus on the effects of metabolic disease and aging. The researchers will also continue to study the functional properties of the hundreds of liver-secreted proteins they cataloged.
“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.
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