Integration of Metabolomics, Lipidomics, and Proteomics Reveals the Metabolic Characterization of Nonalcoholic Steatohepatitis.

ABSTRACT

Metabolic dysfunction is associated with nonalcoholic steatohepatitis (NASH) development. However, omics studies investigating metabolic changes in NASH patients are limited. In this study, metabolomics and lipidomics in plasma, as well as proteomics in the liver, were performed to characterize the metabolic profiles of NASH patients. Moreover, the accumulation of bile acids (BAs) in NASH patients prompted us to investigate the protective effect of cholestyramine on NASH. The liver expression of essential proteins involved in FA transport and lipid droplets was significantly elevated in patients with NASH. Furthermore, we observed a distinct lipidomic remodeling in patients with NASH. We also report a novel finding suggesting an increase in the expression of critical proteins responsible for glycolysis and the level of glycolytic output (pyruvic acid) in patients with NASH. Furthermore, the accumulation of branched chain amino acids, aromatic amino acids, purines, and BAs was observed in NASH patients. Similarly, a dramatic metabolic disorder was also observed in a NASH mouse model. Cholestyramine not only significantly alleviated liver steatosis and fibrosis but also reversed NASH-induced accumulation of BAs and steroid hormones. In conclusion, NASH patients were characterized by perturbations in FA uptake, lipid droplet formation, glycolysis, and accumulation of BAs and other metabolites.