Glutaminase 1 blockade alleviates nonalcoholic steatohepatitis via promoting proline metabolism.
Glutaminase 1 blockade alleviates nonalcoholic steatohepatitis via promoting proline metabolism.
复制标题
谷氨酰胺酶 1 阻断通过促进脯氨酸代谢减轻非酒精性脂肪性肝炎。
DOI：
10.1016/j.bbrc.2022.10.007
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发表时间：
2022
影响因子：
3.1
通讯作者：
Haowen Jiang
中科院分区：
文献类型：
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作者：
Ho;X. Yin;Jingjing Wen;Wenbiao Wu;Bo Zhai;Jinlong Li;Haowen Jiang
非酒精性脂肪性肝炎（NASH）正在成为终末期肝病的主要原因，但目前尚无药物治疗获批，迫切需要开发新的治疗靶点。谷氨酰胺酶1（Glutaminase 1，GLS 1）基因敲减可减轻NASH，但其作用机制尚不清楚。因此，为了探索谷氨酰胺代谢与NASH发展之间的确切关系，我们建立了NASH小鼠模型，并鉴定了经证实的GLS 1抑制剂JHU-083可以有效地减轻NASH。值得注意的是，JHU-083可以通过显著增强脂肪酸氧化能力来降低肝脏中的脂质含量，并且转录组学分析显示JHU-083给药可以影响脯氨酸代谢。然后我们发现JHU-083对脂质代谢的作用依赖于脯氨酸，当脯氨酸代谢被阻断时，GLS 1抑制剂不再起作用。我们的数据表明，抑制谷氨酰胺水解可以通过调节脯氨酸代谢促进脂肪酸氧化，这与NASH的发展密切相关，可以被认为是NASH治疗的新的可能的治疗靶点。
Nonalcoholic steatohepatitis (NASH) is emerging as a major cause of end-stage liver disease, but nowadays no pharmacological therapies are approved and there is an urgent need to develop new therapeutic targets. Glutaminase 1 (GLS1) knockdown had been put forward to alleviate NASH, but its mechanism is still unclear. Herein, to explore the exact relationship between glutamine metabolism and NASH development, we establish a NASH mice model and identified JHU-083, a proven GLS1 inhibitor, could efficiently alleviate NASH. Remarkably, JHU-083 could decrease lipid contents in the liver by enhancing fatty acid oxidation capacity considerably and transcriptomic analysis revealed JHU-083 administration could influence proline metabolism. Then we found the efficacy of JHU-083 on lipid metabolism relied on proline and when proline metabolism was blocked, GLS1 inhibitors no longer worked. Our data suggest that inhibiting glutamine hydrolysis could promote fatty acid oxidation by regulating proline metabolism, which is closely associated with NASH development and could be considered a new possible therapeutic target for NASH therapy.
DOI：
10.1038/nrc.2016.71
发表时间：
2016-10
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Altman BJ;Stine ZE;Dang CV
通讯作者：
Dang CV