Timed secreted proteomes reveal regulation of hepatokines by the liver circadian clock
8 affiliations
- 1Department of Biochemistry & Structural Biology, University of Texas Health San Antonio, San Antonio, TX, USA
- 2Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, USA
- 3Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health San Antonio, San Antonio, TX, USA
- 4Laboratory of Nutritional Biochemistry, Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, Shizuoka, Japan
- 5Department of Cell Systems & Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA
- 6Department of Pathology & Laboratory Medicine, University of Texas Health San Antonio, San Antonio, TX, USA
- 7Department of Biochemistry & Structural Biology, University of Texas Health San Antonio, San Antonio, TX, USA. [email protected]
- 8Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, USA. [email protected]
Abstract
Despite the importance of liver secreted proteins in health and disease, an understanding of their regulation by biological variables such as sex and circadian time is lacking. Here, we validated a well-maintained, dynamic, and unbiased ex vivo assay of liver protein secretion, revealing novel findings. Proteomic analyses uncovered hundreds of sex-dependent hepatokines involved in lipid metabolism, sulfation, and serine protease inhibition, as well as time-dependent hepatokines. Many apolipoproteins and well-characterized plasma proteins were secreted more during daytime, whereas several carboxylesterases and proteins with unconventional secretion tended to be secreted more during nighttime. Time-dependent secreted proteins were transcriptionally regulated by the molecular clock and dysregulated by chronic jet lag-induced circadian misalignment. Finally, we showed that the clock-dependent liver secreted protein endostatin tunes the expression of metabolic genes in white adipose tissue during daytime in female mice. Together, these findings provide key insights into circadian control and sexual dimorphism of liver secreted proteins, which serve as clinical biomarkers and novel therapeutic targets.
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BibTeX
@article{litwin2026timed,
title = {{Timed secreted proteomes reveal regulation of hepatokines by the liver circadian clock}},
author = {Christopher Litwin and Qing Zhang and Ioannis Tsialtas and Zhihong Li and Sophia Hernandez and Steffi Prem and Kristi Dietert and Mallory Keating and Tomoki Sato and Jiyoon Ryu and Lily Dong and Kevin F. Bieniek and Kevin B. Koronowski},
journal = {Nature Communications},
year = {2026},
month = jun,
doi = {10.1038/s41467-026-73840-4},
url = {https://doi.org/10.1038/s41467-026-73840-4},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Timed secreted proteomes reveal regulation of hepatokines by the liver circadian clock
AU - Christopher Litwin
AU - Qing Zhang
AU - Ioannis Tsialtas
AU - Zhihong Li
AU - Sophia Hernandez
AU - Steffi Prem
AU - Kristi Dietert
AU - Mallory Keating
AU - Tomoki Sato
AU - Jiyoon Ryu
AU - Lily Dong
AU - Kevin F. Bieniek
AU - Kevin B. Koronowski
PY - 2026
DA - 2026/06/02
JO - Nature Communications
DO - 10.1038/s41467-026-73840-4
UR - https://doi.org/10.1038/s41467-026-73840-4
AB - Despite the importance of liver secreted proteins in health and disease, an understanding of their regulation by biological variables such as sex and circadian time is lacking. Here, we validated a well-maintained, dynamic, and unbiased ex vivo assay of liver protein secretion, revealing novel findings. Proteomic analyses uncovered hundreds of sex-dependent hepatokines involved in lipid metabolism, sulfation, and serine protease inhibition, as well as time-dependent hepatokines. Many apolipoproteins and well-characterized plasma proteins were secreted more during daytime, whereas several carboxylesterases and proteins with unconventional secretion tended to be secreted more during nighttime. Time-dependent secreted proteins were transcriptionally regulated by the molecular clock and dysregulated by chronic jet lag-induced circadian misalignment. Finally, we showed that the clock-dependent liver secreted protein endostatin tunes the expression of metabolic genes in white adipose tissue during daytime in female mice. Together, these findings provide key insights into circadian control and sexual dimorphism of liver secreted proteins, which serve as clinical biomarkers and novel therapeutic targets.
SN - 2041-1723
ER -