Hepatocyte-to-intestinal stem cell remote communication regulates blood glucose homeostasis

  • Cell Metab. 2026 Jul 7;38(7):1367-1384.e9. doi: 10.1016/j.cmet.2026.05.012.
Jinbao Ye  1 ,  Qianyi Wan  2 ,  Xingzhu Liu  1 ,  Yawen Deng  1 ,  Zehong Zhang  1 ,  Haiou Chen  1 ,  Chaoxin Gao  1 ,  Shiyu Zhang  1 ,  Yuedan Zhu  1 ,  Jinhua Yan  1 ,  Yu Yuan  1 ,  Yi Chen  3 ,  Haiyang Chen  4
Affiliations
  • 1. West China Centre of Excellence for Pancreatitis, and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
  • 2. West China Centre of Excellence for Pancreatitis, and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China; Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3. Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
  • 4. West China Centre of Excellence for Pancreatitis, and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China. Electronic address: [email protected].
PMID: 42309059 DOI: 10.1016/j.cmet.2026.05.012
Abstract

The liver is known to play a pivotal role in modulating blood glucose homeostasis through intrahepatic glucose metabolism. Here, we reveal a unique mechanism by which fatty liver exacerbates hyperglycemia through remote communication from hepatocytes to intestinal stem cells (ISCs), independent of enhanced intrahepatic gluconeogenesis. Mechanistically, hepatocyte-derived Alkaline Phosphatase (ALP) targets α2δ-1 in ISCs to promote the membrane translocation of CAv1.2. This process triggers increased intracellular calcium levels, which subsequently activates the Calcineurin/NFATC2 signaling axis, thereby inhibiting SOX21 expression. Then, decreased expression of SOX21 downregulated bone morphogenetic protein 7 (BMP7), ultimately hindering ISCs differentiation into intestinal L-cells. Consequently, the levels of hypoglycemic enteroendocrine Hormones secreted by L-cells are decreased, thereby promoting hyperglycemia. Therapeutically, inhibiting ALP synthesis in fatty liver independently reduces blood glucose and synergistically enhances the hypoglycemic effect of metformin. Our study highlights the role of liver-gut communication in regulating the fate of ISC differentiation and blood glucose homeostasis.

Keywords
SOX21; alkaline phosphatase; blood glucose; fatty liver; intestinal stem cells.
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