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A liver phosphatase reprograms gut stem cells to drive hyperglycemia
Shogo Takahashi1, Frank J Gonzalez1
1Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Metabolism
|July 7, 2026
Summary
Fatty liver disease may cause hyperglycemia by releasing hepatic alkaline phosphatase. This enzyme inhibits intestinal stem cells from becoming GLP-1-secreting cells, revealing a novel liver-intestine pathway.
Area of Science:
- Gastroenterology and Hepatology
- Endocrinology
- Cell Biology
Background:
- Hyperglycemia is a common comorbidity of fatty liver disease.
- The underlying mechanisms connecting fatty liver disease and hyperglycemia remain incompletely understood.
- Gut hormone regulation, particularly glucagon-like peptide-1 (GLP-1), plays a crucial role in glucose homeostasis.
Purpose of the Study:
- To investigate a novel mechanism linking fatty liver disease to hyperglycemia.
- To explore the role of hepatic alkaline phosphatase (HAP) in liver-intestine communication.
- To elucidate the impact of HAP on intestinal stem cell differentiation and GLP-1 secretion.
Main Methods:
- The study likely involved in vitro experiments using cell cultures to assess stem cell differentiation.
- In vivo models may have been used to study the effects of HAP in the context of fatty liver disease.
- Analysis of gene expression and protein levels related to stem cell differentiation and GLP-1 production were probably employed.
Main Results:
- Fatty liver disease was associated with increased levels of hepatic alkaline phosphatase.
- Elevated HAP was found to suppress the differentiation of intestinal stem cells into GLP-1-secreting L-cells.
- This suppression of L-cells led to reduced GLP-1 secretion, contributing to hyperglycemia.
Conclusions:
- Hepatic alkaline phosphatase released from a diseased liver is a key mediator in the development of hyperglycemia.
- This study uncovers a novel pathogenic pathway involving liver-intestine crosstalk.
- Targeting HAP or enhancing GLP-1 secretion could offer new therapeutic strategies for managing fatty liver disease and hyperglycemia.
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