Regulation of Folate Carrier by Vit D
Folates are essential for brain development and function. Folate transport in mammalian tissues is mediated by three major systems, i.e., reduced folate carrier (RFC), proton-coupled folate transporter (PCFT) and folate receptor alpha (FRα). Brain folate uptake primarily occurs at the choroid plexus through the concerted actions of FRα and PCFT. Inactivating mutations on FRα or PCFT can cause cerebral folate deficiency, resulting in childhood neurodegeneration. Thus, identifying alternative routes for brain folate delivery could lead to therapeutic benefits. This presentation will address the role of RFC in folate uptake at the blood-brain barrier (BBB) and its potential regulation by ligand-activated nuclear receptors such as the vitamin D receptor (VDR), as well as highlight the potential therapeutic role of Vitamin D in the treatment of cerebral folate deficiency, a devastating pediatric neurological condition.
Sensing and Signaling in Kidney Stimulates Gut microbiome-derived OA secretion
Membrane transporters and receptors in the kidney are responsible for balancing nutrient and metabolite levels to aid body homeostasis. We recently discovered that proximal tubule cells in kidneys sense elevated endogenous, gut microbiome-derived, indoxyl sulfate levels through EGF receptors and down-stream signaling to induce their secretion by upregulating the organic anion transporter-1 (OAT1). This presentation will show the remote metabolite sensing and signaling as observed in kidneys from healthy volunteers and rats in vivo, leading to induced OAT1 expression and increased removal of indoxyl sulfate. Further, indoxyl sulfate induces OAT1 via AhR and EGFR signaling, controlled by miR-223 as revealed in 2D and 3D human proximal tubule cell models. In conclusion, remote metabolite sensing and signaling appears to be an effective OAT1 regulation mechanism to maintain plasma indoxyl sulfate levels by controlling its secretion.
Chalk Talk: Investigating Drug Transport and Potential DDIs Using Multi-Transporter Models
This presentation will focus on using multi-transporter models to assist in drug discovery & development, as well as to help answer mechanistic questions about drug disposition.
Folates are essential for brain development and function. Folate transport in mammalian tissues is mediated by three major systems, i.e., reduced folate carrier (RFC), proton-coupled folate transporter (PCFT) and folate receptor alpha (FRα). Brain folate uptake primarily occurs at the choroid plexus through the concerted actions of FRα and PCFT. Inactivating mutations on FRα or PCFT can cause cerebral folate deficiency, resulting in childhood neurodegeneration. Thus, identifying alternative routes for brain folate delivery could lead to therapeutic benefits. This presentation will address the role of RFC in folate uptake at the blood-brain barrier (BBB) and its potential regulation by ligand-activated nuclear receptors such as the vitamin D receptor (VDR), as well as highlight the potential therapeutic role of Vitamin D in the treatment of cerebral folate deficiency, a devastating pediatric neurological condition.
Sensing and Signaling in Kidney Stimulates Gut microbiome-derived OA secretion
Membrane transporters and receptors in the kidney are responsible for balancing nutrient and metabolite levels to aid body homeostasis. We recently discovered that proximal tubule cells in kidneys sense elevated endogenous, gut microbiome-derived, indoxyl sulfate levels through EGF receptors and down-stream signaling to induce their secretion by upregulating the organic anion transporter-1 (OAT1). This presentation will show the remote metabolite sensing and signaling as observed in kidneys from healthy volunteers and rats in vivo, leading to induced OAT1 expression and increased removal of indoxyl sulfate. Further, indoxyl sulfate induces OAT1 via AhR and EGFR signaling, controlled by miR-223 as revealed in 2D and 3D human proximal tubule cell models. In conclusion, remote metabolite sensing and signaling appears to be an effective OAT1 regulation mechanism to maintain plasma indoxyl sulfate levels by controlling its secretion.
Chalk Talk: Investigating Drug Transport and Potential DDIs Using Multi-Transporter Models
This presentation will focus on using multi-transporter models to assist in drug discovery & development, as well as to help answer mechanistic questions about drug disposition.