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

• Published in: Nature communications Vol. 13; no. 1; pp. 5202 - 14
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/31; 13/89; 38; 38/22; 38/77; 38/88; 38/90; 631/80/304; 692/4020/4021/1607/2751; 692/699/2743/2037; 82/58; Age; Age related diseases; Animal models; Animals; Cell culture; Fatty Acids; Fatty liver; Gene expression; Humanities and Social Sciences; Hydroxylase; Life span; Liver; Lysine - metabolism; Mice; Mitochondria; Mitochondria - metabolism; multidisciplinary; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - prevention & control; Oxidation; Peptide Initiation Factors - genetics; Peptide Initiation Factors - metabolism; Polyamines; Post-translation; Protein biosynthesis; Protein synthesis; Proteins; Science; Science (multidisciplinary); Spermidine; Spermidine - pharmacology; Substrates; Therapeutic targets; Translation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32788-x

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 (EIF5A H ). 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 Eif5a H and mitochondrial protein synthesis which leads to lower mitochondrial activity and fatty acid β-oxidation. Spermidine treatment restores EIF5A H , partially restores protein synthesis and mitochondrial function in NASH, and prevents NASH progression in vivo. Thus, the disrupted DHPS-DOHH-EIF5A H 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.