Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression

In patients and mice with non-alcoholic steatohepatitis (NASH), a fatty liver disease characterized by progressive inflammation, hepatocyte injury, and fibrosis, Zhou et al (2022) found decreased hepatic eukaryotic initiation factor 5 A (EIF5A). The decrease in EIF5AH led to decreased synthesis of mitochondrial proteins, reduced mitochondrial activity, and diminished β-oxidation of fatty acids. Spermidine is the sole substrate for hypusination of a lysine residue in EIF5AH, which is critical for protein synthesis. Spermidine treatment preserved Eif5aH in a mouse model of NASH, increased β-oxidation of FA, and partially prevented hepatosteatosis, inflammation, and fibrosis associated with NASH.