Feeding-regulated glycogen metabolism drives rhythmic liver protein secretion
The liver has a key role in inter-organ communication by secreting most circulating plasma proteins. However, the mechanisms governing hepatic protein secretion remain unclear. Here we show that hepatic protein secretion follows a diurnal rhythm regulated by food intake in humans and mice. Using liver microsomal proteomics, we find that proteins implicated in the early secretory pathway, such as protein glycosylation and folding in the endoplasmic reticulum (ER) and Golgi apparatus, exhibit a rhythmic expression profile, which is abolished in Bmal1-knockout mice. Mechanistically, we show that hepatic glycogenolysis provides substrates for protein N-glycosylation. In mice, perturbing hepatic glycogenolysis with pharmacological or nutritional interventions leads to ER stress and attenuates diurnal protein secretion. We confirm these results in humans, as genetic variants associated with glycogen storage disease and congenital disorders of glycosylation also alter hepatic protein secretion. Overall, our work uncovers hepatic glycogen metabolism as a circadian regulator of protein secretion.
Authors
- Glynis Klinke (ORCID: https://orcid.org/0000-0003-2095-4437)
- Mark Larance (ORCID: https://orcid.org/0000-0002-8579-2267)
- Benjamin D. Weger (ORCID: https://orcid.org/0000-0002-1831-3561)
- Iain Templeman (ORCID: https://orcid.org/0000-0002-1684-5943)
- Leonidas G. Karagounis (ORCID: https://orcid.org/0000-0003-2403-3387)
- Robert G. Parton (ORCID: https://orcid.org/0000-0002-7494-5248)
- James Rae (ORCID: https://orcid.org/0000-0003-0525-2154)
- Jean‐Philippe Walhin (ORCID: https://orcid.org/0000-0002-8103-5541)
- Jonathan D. Johnston (ORCID: https://orcid.org/0000-0001-8083-9794)
- Charles Ferguson
- Manfredo Quadroni (ORCID: https://orcid.org/0000-0002-2720-4084)
- James A. Betts (ORCID: https://orcid.org/0000-0002-9129-5777)
- Meltem Weger (ORCID: https://orcid.org/0000-0002-9452-2373)
- Fanny Durussel
- Benjamin L. Schulz (ORCID: https://orcid.org/0000-0002-4823-7758)
- Daniel Mauvoisin (ORCID: https://orcid.org/0000-0003-0571-0741)
- Kyle L. Macauslane (ORCID: https://orcid.org/0000-0002-2725-2609)
- Jingkui Wang
- Michelle Cielesh
- O Muller
- Frédéric Gachon
- Dominic Hoyle
- Dmitri Firsov
- Stephane Fournier
- Eva Martin
Institutions
- Centre National de la Recherche Scientifique (FR)
- The University of Sydney (AU)
- Steno Diabetes Centers (DK)
- Inserm (FR)
- The University of Queensland (AU)
- Aarhus University (DK)
- Heidelberg University (DE)
- University Hospital of Bern (CH)
- University of Surrey (GB)
- Nestlé (Switzerland) (CH)
- Hôpital Nestlé (CH)
- Vienna Biocenter (AT)
- Institut du Thorax (FR)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Bath (GB)
- Australian Catholic University (AU)
- Nantes Université (FR)
- University of Lausanne (CH)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2026-02-05
- DOI
- https://doi.org/10.1038/s42255-026-01453-8
- Primary Topic
- Glycogen Storage Diseases and Myoclonus
- Type
- article
- Field-Weighted Citation Impact
- 0.00