Abstract
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.
Highlights
Introduction βHydroxy-β-methylbutyrate (HMB) is an endogenous minor metabolite of the essential amino acid leucine, a branched-chain amino acid like valine and isoleucine
In vitro studies with cloned transporters expressed heterologously in Xenopus laevis oocytes or mouse muscle cell line C2C12 in culture have shown that HMB is a transportable substrate for the Na+-coupled monocarboxylate transporter SMCT1 (SLC5A8) and the H+-coupled monocarboxylate transporters MCT1 (SLC16A1) and MCT4 (SLC16A3) [15]
Since a previously published report implicated MCT1, MCT4, and SMCT1 in HMB uptake in muscle cells [15], we examined the expressions of these three transporters in hCMEC/D3 cells (Figure 1C)
Summary
Introduction βHydroxy-β-methylbutyrate (HMB) is an endogenous minor metabolite of the essential amino acid leucine, a branched-chain amino acid like valine and isoleucine. The metabolism of all three branched-chain amino acids occurs robustly in the liver, and in the skeletal muscle, brain, and retina [1,2,3]. The circulating levels or tissue levels of HMB are in the low micromolar range under normal physiological conditions. This minor metabolite has been found to have a significant impact on the cellular signaling pathways associated with anabolic metabolism, but only at supra-physiological concentrations [4,5,6]. The anti-obesity effect of orally administered HMB might arise from the influence of bacteria-generated propionate on organs such as the intestinal tract, liver and adipocytes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
