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Fenofibrate reduces glucose-induced barrier dysfunction in feline enteroids
Charles K Crawford1, Aeelin Beltran1, Diego Castillo1
1Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA, USA.
Scientific Reports
|December 18, 2023
Summary
Persistent hyperglycemia in diabetes mellitus directly damages the intestinal barrier by disrupting tight junctions. Fenofibrate treatment mitigates this damage, offering a potential therapeutic strategy for diabetic intestinal dysfunction.
Area of Science:
- Gastroenterology
- Endocrinology
- Cell Biology
Background:
- Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia, often leading to intestinal barrier dysfunction.
- The intestinal barrier's integrity, regulated by tight junctions, is crucial for preventing paracellular movement of harmful substances.
- The direct impact of hyperglycemia on intestinal epithelial cells and barrier function remains incompletely understood.
Purpose of the Study:
- To investigate the direct effects of hyperglycemia on feline intestinal epithelial barrier function.
- To determine if fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, can ameliorate hyperglycemia-induced intestinal barrier dysfunction.
- To elucidate the role of protein kinase C-alpha (PKCα) in mediating these effects.
Main Methods:
- Utilized feline intestinal organoids to model hyperglycemia-like conditions.
- Assessed intestinal epithelial permeability and tight junction morphology.
- Measured protein kinase C-alpha (PKCα) activity in response to glucose and fenofibrate treatments.
Main Results:
- Hyperglycemia-like conditions significantly increased intestinal epithelial permeability.
- This increased permeability was associated with disrupted tight junctions, evidenced by increased junctional tortuosity.
- Fenofibrate treatment mitigated hyperglycemia-induced permeability and restored normal tight junction structure.
- Fenofibrate normalized elevated PKCα activity observed under hyperglycemic conditions.
Conclusions:
- Hyperglycemia directly impairs intestinal barrier function by disrupting tight junction structure.
- Fenofibrate effectively ameliorates hyperglycemia-induced intestinal barrier dysfunction.
- Modulation of protein kinase C-alpha (PKCα) activity by glucose and fenofibrate is a key pathway regulating tight junction integrity and epithelial permeability in diabetes.
