Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression.
Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression.
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DOI：
10.1038/s41467-022-32788-x
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发表时间：
2022-09-03
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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亚精胺是一种天然的多胺，对健康有好处，并在几个物种中延长寿命。脱氧亚硫氨酸合成酶(DHPs)和脱氧亚精氨酸羟基酶(DOHH)是利用亚精胺催化翻译因子EIF5A(EIF5AH)翻译后亚苏化的关键酶。在这里，我们发现在非酒精性脂肪性肝炎(NASH)患者和小鼠以及用脂肪酸治疗的肝细胞中，肝脏DOHH mRNA的表达减少。NASH的小鼠模型和细胞培养模型伴随着Eif5aH和线粒体蛋白质合成的降低，从而导致线粒体活性降低和脂肪酸β氧化。亚精胺治疗可恢复EIF5AH，部分恢复NASH的蛋白质合成和线粒体功能，并阻止体内NASH的进展。因此，NASH过程中DHPS-DOHH-EIF5AH通路的中断代表了增加肝脏蛋白质合成和线粒体脂肪酸氧化(FAO)和防止NASH进展的治疗靶点。亚精胺是一种多胺，据报道可以延长寿命并降低与年龄相关的疾病的风险，它是翻译后修饰炒作的底物。在此，作者报道了在非酒精性脂肪性肝炎(NASH)过程中，调节线粒体蛋白质合成的EIF5A激活减少，这可以通过亚精胺来阻止NASH在小鼠中的进展。
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.
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影响因子：
3.5
作者：
Nishimura, Kazuhiro;Lee, Seung Bum;Park, Jong Hwan;Park, Myung Hee
通讯作者：
Park, Myung Hee
影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
影响因子：
25.7
作者：
Gan, Lay T.;Van Rooyen, Derrick M.;Farrell, Geoffrey C.
通讯作者：
Farrell, Geoffrey C.
影响因子：
3.8
作者：
Lake, April D.;Novak, Petr;Cherrington, Nathan J.
通讯作者：
Cherrington, Nathan J.
DOI：
10.1038/s41580-018-0033-y
发表时间：
2018-09
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Hansen M;Rubinsztein DC;Walker DW
通讯作者：
Walker DW