# Feeding-regulated glycogen metabolism drives rhythmic liver protein secretion

## TL;DR

The liver's protein secretion follows a daily rhythm controlled by feeding and glycogen metabolism, impacting overall health.

## Contribution

This study reveals that glycogen metabolism regulates rhythmic liver protein secretion through glycosylation.

## Key findings

- Hepatic protein secretion follows a diurnal rhythm regulated by food intake in humans and mice.
- Glycogenolysis provides substrates for protein N-glycosylation, and its disruption causes ER stress and reduced secretion.
- Genetic variants related to glycogen storage and glycosylation disorders alter hepatic protein secretion in humans.

## Abstract

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.

Hepatic glycogenolysis is essential for protein glycosylation and rhythmic secretion by the liver. Disruptions to hepatic glycogenolysis, caused by congenital diseases or physiological factors such as obesity, caloric restriction and changes to meal timing, alter hepatic protein secretion.