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- Title
Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression.
- Authors
Zhou, Jin; Pang, Jeremy; Tripathi, Madhulika; Ho, Jia Pei; Widjaja, Anissa Anindya; Shekeran, Shamini Guna; Cook, Stuart Alexander; Suzuki, Ayako; Diehl, Anna Mae; Petretto, Enrico; Singh, Brijesh Kumar; Yen, Paul Michael
- Abstract
Spermidine is a natural polyamine that has health benefits and extends life span in several species. Deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH) are key enzymes that utilize spermidine to catalyze the post-translational hypusination of the translation factor EIF5A (EIF5AH). Here, we have found that hepatic DOHH mRNA expression is decreased in patients and mice with non-alcoholic steatohepatitis (NASH), and hepatic cells treated with fatty acids. The mouse and cell culture models of NASH have concomitant decreases in Eif5aH and mitochondrial protein synthesis which leads to lower mitochondrial activity and fatty acid β-oxidation. Spermidine treatment restores EIF5AH, partially restores protein synthesis and mitochondrial function in NASH, and prevents NASH progression in vivo. Thus, the disrupted DHPS-DOHH-EIF5AH pathway during NASH represents a therapeutic target to increase hepatic protein synthesis and mitochondrial fatty acid oxidation (FAO) and prevent NASH progression. Spermidine, a polyamine reported to extend lifespan and reduce the risk of age-related diseases, serves as a substrate for the post-translational modification hypusination. Here the authors report that EIF5A hypusination, which regulates mitochondrial protein synthesis, is reduced during non-alcoholic steatohepatitis (NASH), which can be prevented by spermidine to inhibit the progression of NASH in mice.
- Subjects
FATTY acid oxidation; NON-alcoholic fatty liver disease; CELL culture; POST-translational modification; MITOCHONDRIAL proteins; POLYAMINES; PROTEIN synthesis
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-32788-x