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Cellular retinoic acid bioavailability in various pathologies and its therapeutic implication
1Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Abstract:
Retinoic acid (RA), an active metabolite of vitamin A, is a critical signaling molecule in various cell types. We found that RA depletion caused by expression of the RA-metabolizing enzyme CYP26A1 promotes carcinogenesis, implicating CYP26A1 as a candidate oncogene. Several studies of CYP26s have suggested that the biological effect of RA on target cells is primarily determined by "cellular RA bioavailability", which is defined as the RA level in an individual cell, rather than by the serum concentration of RA. Consistently, stellate cells store approximately 80% of vitamin A in the body, and the state of cellular RA bioavailability regulates their function. Based on the similarities between stellate cells and astrocytes, we demonstrated that retinal astrocytes regulate tight junction-based endothelial integrity in a paracrine manner. Since diabetic retinopathy is characterized by increased vascular permeability in its early pathogenesis, RA normalized retinal astrocytes that are compromised in diabetes, resulting in suppression of vascular leakiness. RA also attenuated the loss of the epithelial barrier in murine experimental colitis. The concept of "cellular RA bioavailability" in various diseases will be directed at understanding various pathologies caused by RA insufficiency, implying the potential feasibility of a therapeutic strategy targeting the stellate cell system.
Insights
Retinoic acid (RA) depletion promotes cancer by affecting cellular RA bioavailability. Restoring RA levels in retinal astrocytes and epithelial cells can prevent vascular leakiness and barrier loss in diseases like diabetic retinopathy and colitis.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Retinoic acid (RA), a vitamin A metabolite, is crucial for cell signaling.
- Cellular RA bioavailability, not serum levels, dictates RA's biological effects.
- Stellate cells store vitamin A and regulate cellular RA bioavailability.
Purpose of the Study:
- To investigate the role of RA depletion in carcinogenesis via CYP26A1.
- To explore the function of retinal astrocytes in vascular integrity.
- To assess RA's therapeutic potential in diseases with compromised barriers.
Main Methods:
- Investigated the effect of CYP26A1 expression on carcinogenesis.
- Examined the paracrine regulation of endothelial integrity by retinal astrocytes.
- Assessed RA's impact on vascular leakiness in diabetic retinopathy models.
- Evaluated RA's effect on epithelial barrier integrity in experimental colitis.
Main Results:
- CYP26A1-mediated RA depletion promotes carcinogenesis, identifying it as a candidate oncogene.
- Retinal astrocytes regulate endothelial integrity, and RA normalizes compromised astrocytes in diabetes.
- RA suppresses vascular leakiness in diabetic retinopathy and attenuates epithelial barrier loss in colitis.
Conclusions:
- Cellular RA bioavailability is critical in regulating cellular functions and disease pathogenesis.
- Targeting the stellate cell system and enhancing cellular RA bioavailability offers a potential therapeutic strategy for RA-insufficiency diseases.