Hydrogen Activates ATP-Binding Cassette Transporter A1-Dependent Efflux Ex Vivo and Improves High-Density Lipoprotein Function in Patients With Hypercholesterolemia: A Double-Blinded, Randomized, and Placebo-Controlled Trial

CONTEXT: We have found that hydrogen (dihydrogen [H2]) decreases plasma low-density lipoprotein (LDL) cholesterol levels and improves high-density lipoprotein (HDL) function in patients with potential metabolic syndrome in a before-after self-controlled study. OBJECTIVE: The purpose of this study was to further characterize the effects of H2-rich water (0.9 L/day) on the content, composition, and biological activities of plasma lipoproteins on patients with hypercholesterolemia and their underlying mechanisms in a double-blinded, randomized, and placebo-controlled trial. DESIGN: This was a case-control study. SETTING: The setting was the Zhoudian community, Tai'an, China. PATIENTS: A total of 68 patients with untreated isolated hypercholesterolemia were randomly allocated to either drinking H2-rich water (n = 34) or placebo water (n = 34) for 10 weeks. RESULTS: HDL isolated from the H2 group showed an increased ability to promote the ATP-binding cassette transporter A1-mediated cholesterol efflux ex vivo. Plasma pre-β-HDL levels were up-regulated although there were no changes in plasma HDL-cholesterol levels. Moreover, other HDL functions, assessed in protection against LDL oxidation, inhibition of oxidized-LDL-induced inflammation, and protection of endothelial cells from oxidized-LDL-induced apoptosis, were all significantly improved by H2 treatment. In addition, H2 treatment increased the effective rate in down-regulating plasma levels of total cholesterol (47.06% vs 17.65%) and LDL cholesterol (47.06% vs 23.53%). Western blot analysis revealed a marked decrease in apolipoprotein B100 and an increase in apolipoprotein M in plasma of the H2 group. Finally H2 treatment resulted in a significant reduction in the levels of several inflammatory and oxidative stress indicators in whole plasma and HDL particles. CONCLUSIONS: H2 activates ATP-binding cassette transporter A1-dependent efflux, enhances HDL antiatherosclerotic functions, and has beneficial lipid-lowering effects. The present findings highlight the potential role of H2 in the regression of hypercholesterolemia and atherosclerosis.