Liver's Internal Clock Governs Timed Release of Metabolism-Regulating Proteins, Pointing to Chronotherapy for Metabolic Disease
核心洞察
Researchers at UT Health San Antonio found that the liver's internal circadian clock controls the timed release of metabolism-regulating signaling proteins, published in Nature Communications.
The liver protein endostatin proved most effective at promoting fat breakdown when released on its natural daily rhythm, suggesting time-of-day dosing could matter for future therapies.
Irregular eating and disrupted sleep are linked to higher risks of obesity (搜索), diabetes (搜索), and other metabolic disorders, underscoring the clinical relevance of circadian coordination.
The liver runs metabolism on a surprisingly precise timetable, releasing signaling proteins at specific points in the day rather than at random. Researchers at UT Health San Antonio, the academic health center of The University of Texas at San Antonio (UT San Antonio), have demonstrated that the liver's internal clock controls when metabolism-regulating proteins are secreted, a discovery that could reshape how metabolic disease, meal timing, and medication scheduling are approached.
The study, published June 2 in Nature Communications, found that many of these proteins follow a precise daily release schedule. This timing allows the liver to communicate with other organs, including fat tissue, at particular times of day.
"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 the Joe R. and Teresa Lozano Long School of Medicine and 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."
The Liver Clock Coordinates Metabolism
Irregular eating patterns and disrupted sleep schedules have long been associated with higher risks of obesity (搜索), diabetes (搜索), and other metabolic disorders. Because the liver is central to metabolism, the researchers set out to determine how its internal clock controls the secretion of proteins that carry signals to other organs.
Nearly every cell in the body has its own molecular clock, which helps organize daily functions such as metabolism, but researchers are still working to understand how these cellular clocks coordinate with one another. Christopher Litwin, a fourth-year PhD student in Koronowski's lab and the study's first author, noted that researchers already knew the liver controls the secretion of some proteins, but they lacked a detailed way to measure how and when that release occurs.
"We thought the time-dependent release of proteins may be important for coordinating metabolism in tissues like fat or muscle," said Litwin. "The core idea is that the clock regulates protein secretion and can influence metabolism across the day, and in other tissues."
Endostatin Works Best on Schedule
A key finding involved endostatin, a protein released by the liver. It was most effective at promoting fat breakdown when its release followed the liver's natural daily rhythm, suggesting that treatments based on the protein might work differently depending on the time of day they are administered. The finding points toward a chronotherapeutic principle in which the timing of administration could influence efficacy.
The researchers are continuing to investigate approaches that could eventually have therapeutic applications. "We are interested in developing and characterizing novel peptides. We want to find the next GLP-1 (搜索) drug, or even something better that is waiting to be discovered," said Koronowski.
The study, titled "Timed secreted proteomes reveal regulation of hepatokines by the liver circadian clock," was authored by Christopher Litwin, Qing Zhang, Ioannis Tsialtas, Zhihong Li, Sophia Hernandez, Steffi Prem, Kristi Dietert, Mallory Keating, Tomoki Sato, Jiyoon Ryu, Lily Q. Dong, Kevin F. Bieniek, and Kevin B. Koronowski.