Long-term and daily use of molecular hydrogen induces reprogramming of liver metabolism in rats by modulating NADP/NADPH redox pathways

Molecular hydrogen (H 2 ) has emerged as a new therapeutic option in several diseases and is widely adopted by healthy people. However, molecular data to support therapeutic functions attributed to the biological activities of H 2 remain elusive. Here, using transcriptomic and metabolomic approaches coupled with biochemistry and micro-CT technics, we evaluated the effect of long-term (6 months) and daily use of H 2 on liver function. Rats exposed 2 h daily to H 2 either by drinking HRW (H 2 dissolved in H 2 O) or by breathing 4% H 2 gas showed reduced lipogenesis and enhanced lipolysis in the liver, which was associated with apparent loss of visceral fat and brown adipose tissue together with a reduced level of serum lipids. Both transcripts and metabolites enriched in H 2 -treated rats revealed alteration of amino acid metabolism pathways and activation of purine nucleotides and carbohydrate biosynthesis pathways. Analysis of the interaction network of genes and metabolites and correlation tests revealed that NADP is the central regulator of H 2 induced metabolic alterations in the liver, which was further confirmed by an increase in the level of components of metabolic pathways that require NADP as substrate. Evidence of immune response regulation activity was also observed in response to exposure to H 2 . This work is the first to provide metabolomic and transcriptomic data to uncover molecular targets for the effect of prolonged molecular hydrogen treatment on liver metabolism.