Pegylated arginine deiminase drives arginine turnover and systemic autophagy to dictate energy metabolism.
Pegylated arginine deiminase drives arginine turnover and systemic autophagy to dictate energy metabolism.
复制标题
聚乙二醇化的精氨酸脱亚胺酶驱动精氨酸周转和全身性自噬来控制能量代谢。
DOI：
10.1016/j.xcrm.2021.100498
复制
发表时间：
2022-01-18
期刊：
影响因子：
--
通讯作者：
DeBosch BJ
中科院分区：
文献类型：
--
作者：
Zhang Y;Higgins CB;Van Tine BA;Bomalaski JS;DeBosch BJ
肥胖是一种多系统的能量平衡紊乱。尽管进行了深入的研究，能量稳态的决定因素仍然不完全清楚，并且缺乏针对肥胖及其并发症的有效治疗方法。在这里，我们证明了细菌毒力因子和精氨酸脱亚胺酶（arcA）的赋予精氨酸亚胺水解，促进了哺乳动物的能量消耗和胰岛素敏感性，并逆转了肥胖小鼠的血脂异常、肝脂肪变性和炎症。进一步，通过聚乙二醇化精氨酸脱亚胺酶（ADI-PEG - 20）的药理学精氨酸分解代谢在饮食和遗传肥胖模型中概括了这些代谢作用。这些作用需要自噬复合物蛋白BECN1在肝脏和全身的表达以及肝细胞特异性FGF21的分泌。单细胞ATAC测序进一步揭示了becn1依赖性肝细胞染色质可及性对ADI-PEG 20的响应变化。因此，这些数据揭示了精氨酸分解代谢通过激活全身自噬来调节能量代谢的意想不到的治疗效用，这现在可以通过现成的药物治疗来利用。聚乙二醇化精氨酸脱亚胺酶（ADI-PEG 20）目前用于治疗肝脏肿瘤。ADI-PEG 20改善胰岛素敏感性、血脂异常、ADI-PEG 20通过驱动全身和肝细胞自噬改善能量稳态。精氨酸分解代谢是治疗肥胖及相关疾病的一种易处理的途径。Zhang等人研究表明，通过表达肝细胞精氨酸脱亚胺酶或用ADI-PEG 20药物治疗小鼠，促进全身精氨酸分解代谢，诱导全身和肝脏自噬流，从而改善小鼠肥胖及其并发症。
Obesity is a multi-systemic disorder of energy balance. Despite intense investigation, the determinants of energy homeostasis remain incompletely understood, and efficacious treatments against obesity and its complications are lacking. Here, we demonstrate that conferred arginine iminohydrolysis by the bacterial virulence factor and arginine deiminase, arcA, promotes mammalian energy expenditure and insulin sensitivity and reverses dyslipidemia, hepatic steatosis, and inflammation in obese mice. Extending this, pharmacological arginine catabolism via pegylated arginine deiminase (ADI-PEG 20) recapitulates these metabolic effects in dietary and genetically obese models. These effects require hepatic and whole-body expression of the autophagy complex protein BECN1 and hepatocyte-specific FGF21 secretion. Single-cell ATAC sequencing further reveals BECN1-dependent hepatocyte chromatin accessibility changes in response to ADI-PEG 20. The data thus reveal an unexpected therapeutic utility for arginine catabolism in modulating energy metabolism by activating systemic autophagy, which is now exploitable through readily available pharmacotherapy. Pegylated arginine deiminase (ADI-PEG 20) is currently used to treat liver tumors ADI-PEG 20 improves insulin sensitivity, dyslipidemia, and liver fat in obese mice ADI-PEG 20 improves energy homeostasis by driving systemic and hepatocyte autophagy Arginine catabolism is a tractable pathway to treat obesity and related disorders Zhang et al. show that promoting systemic arginine catabolism by expressing hepatocyte arginine deiminase—or by treating mice with the drug ADI-PEG 20—induces systemic and hepatic autophagic flux to ameliorate obesity and its complications in mice.
登录
查看更多内容
影响因子：
19
作者：
Funderburk SF;Wang QJ;Yue Z
通讯作者：
Yue Z
DOI：
10.1073/pnas.1404171111
发表时间：
2014-09-30
影响因子：
11.1
作者：
Changou, Chun A.;Chen, Yun-Ru;Kung, Hsing-Jien
通讯作者：
Kung, Hsing-Jien
影响因子：
3
作者：
Harding, James J.;Do, Richard K.;Abou-Alfa, Ghassan K.
通讯作者：
Abou-Alfa, Ghassan K.
影响因子：
44.5
作者：
Clement, Karine;van den Akker, Erica;Kuehnen, Peter
通讯作者：
Kuehnen, Peter
影响因子：
20.8
作者：
Flippo KH;Potthoff MJ
通讯作者：
Potthoff MJ