Major involvement of Na⁺‐dependent multivitamin transporter (SLC5A6/SMVT) in uptake of biotin and pantothenic acid by human brain capillary endothelial cells

Abstract

The purpose of this study was to clarify the expression of Na + -dependent multivitamin transporter (SLC5A6/SMVT) and its contribution to the supply of biotin and pantothenic acid to the human brain via the blood-brain barrier. DNA microarray and immunohistochemical analyses confirmed that SLC5A6 is expressed in microvessels of human brain. by human cerebral microvascular endothelial cell line hCMEC/ D3. SLC5A6-mediated transport in hCMEC/D3 was markedly inhibited not only by biotin and pantothenic acid, but also by prostaglandin E2, lipoic acid, docosahexaenoic acid, indomethacin, ketoprofen, diclofenac, ibuprofen, phenylbutazone, and flurbiprofen. This study is the first to confirm expression of SLC5A6 in human brain microvessels and to provide evidence that SLC5A6 is a major contributor to luminal uptake of biotin and pantothenic acid at the human blood-brain barrier. Keywords: biotin, human blood-brain barrier, luminal uptake, pantothenic acid, SLC5A6, structure of inhibitor.

Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child

“…The hSMVT system transports three important nutrients: the water-soluble vitamins biotin and pantothenic acid, and the metabolically important substrate, lipoate (Prasad et al 1997; Uchida et al 2015; Zehnfenning et al 2015). These nutrients are involved in multiple essential metabolic functions, including intermediary metabolism, protein synthesis, bone density and brain and immune function (Bonjour 1980; Uchida et al . 2015; Moiseenok et al 2000; Palaniyappan and Alphonese 2011).…”

“…This result was due to severe reduction in the level of expression of the R94X mutant, and to retention of the R123L mutant protein in the endoplasmic reticulum of cells. Since hSMVT is involved in the delivery of not only biotin but also lipoate (Uchida et al 2015), and likely pantothenic acid, impairment in the transport function of this carrier is expected to affect the transport of all three nutrients.…”

“…This gene is located on chromosome 2, and the hSMVT protein is predicted to have 12 trans-membrane domains (TMD) with both the NH 2 and COOH termini facing the cell interior (Wang et al 1999). The hSMVT system also transports the water-soluble vitamin pantothenic acid (Prasad et a l. 1997; Uchida et al . 2015) and the metabolically important lipoate (Prasad et al .…”

A Novel Anti-Hepatitis C Virus and Antiproliferative Agent Alters Metabolic Networks in HepG2 and Hep3B Cells

“…It is surmised that compound 3b increases CoA synthesis by enhancing SLC5A6 activity to increase pantothenic acid transport from the culture medium, where it is present at a concentration of 16.8 μM. SLC5A6 accounts for 98.6% of pantothenic acid uptake across the human blood-brain barrier and has been studied in detail in a human microvascular endothelial cell line [37]. The most potent drug inhibitors of SLC5A6 were reported to be NSAIDs, including indomethacin, ketoprofen, diclofenac, ibuprofen, phenylbutazone, and flurbiprofen [37].…”

“…SLC5A6 accounts for 98.6% of pantothenic acid uptake across the human blood-brain barrier and has been studied in detail in a human microvascular endothelial cell line [37]. The most potent drug inhibitors of SLC5A6 were reported to be NSAIDs, including indomethacin, ketoprofen, diclofenac, ibuprofen, phenylbutazone, and flurbiprofen [37]. Diflunisal is an NSAID and, thus, is therefore potentially a greater inhibitor of pantothenic acid uptake by HepG2 cells than compound 3b.…”