Rab4b controls hepatic glucose production during fasting through glycophagy
Abstract
Hepatic glucose production, essential for maintaining glycemia, is often altered in metabolic-associated fatty liver and glycogen storage diseases. Therefore, understanding the mechanisms that regulate the glucose production by hepatocyte is pivotal. Recent studies have identified endocytic trafficking as a key modulator of liver glucose production. Particularly, its role in directing protein trafficking toward lysosomal degradation influences gluconeogenesis. However, the contribution of endocytic recycling to liver glucose production remains yet poorly understood. Here, we demonstrate that hepatocyte-specific disruption of endocytic recycling, achieved through Rab4b knockout in male, leads to fasting hyperglycemia. Mechanistically, hepatocytes lacking Rab4b exhibit an increased capacity to produce glucose independently of gluconeogenesis by depleting their glycogen stores. This is driven by enhanced glycophagy, leading to excessive glucose release and fasting hyperglycemia. Notably, liver Rab4b expression also correlates with glycemia in both mice and human, highlighting a critical role of Rab4b-dependent endocytic recycling in regulating blood glucose homeostasis during fasting.
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BibTeX
@article{dussot2026rab4b,
title = {{Rab4b controls hepatic glucose production during fasting through glycophagy}},
author = {Marion Dussot and Lucie Le Parc and Sihame Sabbane and Alycia Zedda and Abderrahman Chafik and Alexandre Gallerand and Karine Dumas and Stéphanie Bonnafous and Yun Kwon and Sandra Lacas-Gervais and Charlotte Hinault Boyer and Giulia Chinetti and Sophie Giorgetti-Peraldi and Philippe Gual and Stoyan Ivanov and Anja Zeigerer and Jean-François Tanti and Mireille Cormont and Jerome Gilleron},
journal = {Nature Communications},
year = {2026},
month = aug,
doi = {10.1038/s41467-026-76218-8},
url = {https://hal.science/hal-05744040v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Rab4b controls hepatic glucose production during fasting through glycophagy
AU - Marion Dussot
AU - Lucie Le Parc
AU - Sihame Sabbane
AU - Alycia Zedda
AU - Abderrahman Chafik
AU - Alexandre Gallerand
AU - Karine Dumas
AU - Stéphanie Bonnafous
AU - Yun Kwon
AU - Sandra Lacas-Gervais
AU - Charlotte Hinault Boyer
AU - Giulia Chinetti
AU - Sophie Giorgetti-Peraldi
AU - Philippe Gual
AU - Stoyan Ivanov
AU - Anja Zeigerer
AU - Jean-François Tanti
AU - Mireille Cormont
AU - Jerome Gilleron
PY - 2026
DA - 2026/08/10
JO - Nature Communications
DO - 10.1038/s41467-026-76218-8
UR - https://hal.science/hal-05744040v1
AB - Hepatic glucose production, essential for maintaining glycemia, is often altered in metabolic-associated fatty liver and glycogen storage diseases. Therefore, understanding the mechanisms that regulate the glucose production by hepatocyte is pivotal. Recent studies have identified endocytic trafficking as a key modulator of liver glucose production. Particularly, its role in directing protein trafficking toward lysosomal degradation influences gluconeogenesis. However, the contribution of endocytic recycling to liver glucose production remains yet poorly understood. Here, we demonstrate that hepatocyte-specific disruption of endocytic recycling, achieved through Rab4b knockout in male, leads to fasting hyperglycemia. Mechanistically, hepatocytes lacking Rab4b exhibit an increased capacity to produce glucose independently of gluconeogenesis by depleting their glycogen stores. This is driven by enhanced glycophagy, leading to excessive glucose release and fasting hyperglycemia. Notably, liver Rab4b expression also correlates with glycemia in both mice and human, highlighting a critical role of Rab4b-dependent endocytic recycling in regulating blood glucose homeostasis during fasting.
SN - 2041-1723
SN - 2041-1723
ER -