Metabolomics reveals the defense mechanism of histidine supplementation on high-salt exposure-induced hepatic oxidative stress.

AIMS

This study mainly evaluated the protective mechanism of histidine against the hepatic oxidative stress after high-salt exposure (HSE) through combined analysis of non-targeted metabolomics and biological metabolic networks.

MATERIALS AND METHODS

Dahl salt-sensitive (SS) rats were fed with normal-salt diet or HSE ± histidine in addition to drinking water for 14 days. Gas chromatography-mass spectrometry was used to analyze the hepatic metabolites. The metabolic profile was analyzed by SIMCA-14.1, the metabolic correlation network was performed using Gephi-0.9.2, and pathway enrichment was analyzed using MetaboAnalyst 5.0 online website.

KEY FINDINGS

Results indicated that HSE disturbed the hepatic metabolic profile, generated abnormal liver metabolism and exacerbated oxidative stress. Histidine supplementation significantly reversed the hepatic metabolic profile. Of note, 14 differential metabolic pathways were enriched after histidine supplementation, most of which played an important role in ameliorating redox and nitric oxide (NO) metabolism. Histidine administration decreased the levels of hydroperoxide and malondialdehyde, and increased the activities of antioxidant enzymes (Catalase, Superoxide Dismutase, Glutathione S-transferase and Glutathione reductases). Histidine effectively enhanced the endogenous synthesis of glutathione by increasing the levels of glutamate and cysteine, thereby enhancing the antioxidant capacity of the glutathione system. After histidine administration, lysine, glutamate, and hypotaurine owned a higher metabolic centrality in the correlation network. In addition, histidine could also effectively increase the endogenous synthesis of NO by enhancing the -arginine/NO pathway.

SIGNIFICANCE

This study offers new insights into the metabolic mechanisms underlying the antioxidant protective effect of histidine on the liver.