Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
Abbott Nutrition, Research & Development, 18004 Granada, Spain.
Nutrients. 2021 Sep 16;13(9):3220. doi: 10.3390/nu13093220.
β-Hydroxy-β-methylbutyrate (HMB), a leucine metabolite, is used as a nutritional ingredient to improve skeletal muscle health. Preclinical studies indicate that this supplement also elicits significant benefits in the brain; it promotes neurite outgrowth and prevents age-related reductions in neuronal dendrites and cognitive performance. As orally administered HMB elicits these effects in the brain, we infer that HMB crosses the blood-brain barrier (BBB). However, there have been no reports detailing the transport mechanism for HMB in BBB. Here we show that HMB is taken up in the human BBB endothelial cell line hCMEC/D3 via H-coupled monocarboxylate transporters that also transport lactate and β-hydroxybutyrate. MCT1 (monocarboxylate transporter 1) and MCT4 (monocarboxylate transporter 4) belonging to the solute carrier gene family SLC16 (solute carrier, gene family 16) are involved, but additional transporters also contribute to the process. HMB uptake in BBB endothelial cells results in intracellular acidification, demonstrating cotransport with H. Since HMB is known to activate mTOR with potential to elicit transcriptomic changes, we examined the influence of HMB on the expression of selective transporters. We found no change in MCT1 and MCT4 expression. Interestingly, the expression of LAT1 (system L amino acid transporter 1), a high-affinity transporter for branched-chain amino acids relevant to neurological disorders such as autism, is induced. This effect is dependent on mTOR (mechanistic target of rapamycine) activation by HMB with no involvement of histone deacetylases. These studies show that HMB in systemic circulation can cross the BBB via carrier-mediated processes, and that it also has a positive influence on the expression of LAT1, an important amino acid transporter in the BBB.
β-羟基-β-甲基丁酸（HMB）是亮氨酸的代谢产物，被用作营养成分以改善骨骼肌健康。临床前研究表明，这种补充剂对大脑也有显著的益处；它促进神经突生长，并防止与年龄相关的神经元树突减少和认知表现下降。由于口服 HMB 会在大脑中引起这些作用，我们推断 HMB 可以穿过血脑屏障（BBB）。然而，目前还没有详细报道 HMB 在 BBB 中的转运机制。在这里，我们表明 HMB 通过 H 偶联单羧酸转运体被摄取到人类 BBB 内皮细胞系 hCMEC/D3 中，这些转运体也可以转运乳酸和 β-羟基丁酸。属于溶质载体基因家族 SLC16（溶质载体，基因家族 16）的 MCT1（单羧酸转运蛋白 1）和 MCT4（单羧酸转运蛋白 4）参与了这个过程，但其他转运体也对此过程有贡献。BBB 内皮细胞中的 HMB 摄取导致细胞内酸化，证明与 H 共转运。由于 HMB 已知可以激活 mTOR，从而有可能引发转录组变化，因此我们研究了 HMB 对选择性转运体表达的影响。我们没有发现 MCT1 和 MCT4 表达的变化。有趣的是，LAT1（系统 L 氨基酸转运蛋白 1）的表达被诱导，LAT1 是一种与自闭症等神经紊乱相关的支链氨基酸的高亲和力转运体。这种作用依赖于 HMB 激活 mTOR，而不涉及组蛋白去乙酰化酶。这些研究表明，循环系统中的 HMB 可以通过载体介导的过程穿过 BBB，并且它还对 LAT1 的表达有积极影响，LAT1 是 BBB 中的一种重要氨基酸转运体。
