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

Jin Zhou (), Jeremy Pang, Madhulika Tripathi, Jia Pei Ho, Anissa Anindya Widjaja, Shamini Guna Shekeran, Stuart Alexander Cook, Ayako Suzuki, Anna Mae Diehl, Enrico Petretto, Brijesh Kumar Singh and Paul Michael Yen ()
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Jin Zhou: Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School Singapore
Jeremy Pang: Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School Singapore
Madhulika Tripathi: Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School Singapore
Jia Pei Ho: Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School Singapore
Anissa Anindya Widjaja: Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School Singapore
Shamini Guna Shekeran: Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School Singapore
Stuart Alexander Cook: Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School Singapore
Ayako Suzuki: Duke University School of Medicine
Anna Mae Diehl: Duke University School of Medicine
Enrico Petretto: Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School Singapore
Brijesh Kumar Singh: Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School Singapore
Paul Michael Yen: Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School Singapore

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32788-x

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