Hepatic and intestinal manganese excretion are both required to regulate brain manganese during elevated manganese exposure.
Hepatic and intestinal manganese excretion are both required to regulate brain manganese during elevated manganese exposure.
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在锰暴露升高期间，肝脏和肠道的锰排泄都是调节脑锰所必需的。
DOI：
10.1152/ajpgi.00047.2023
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Mukhopadhyay,Somshuvra
中科院分区：
文献类型：
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作者：
Hutchens,Steven;Jursa,ThomasP;Melkote,Ashvini;Grant,StephanieM;Smith,DonaldR;Mukhopadhyay,Somshuvra
锰（Mn）是必需的，但在升高的水平下具有神经毒性。在生理条件下，Mn主要由肝脏排泄，肠道起次要作用。最近对组织特异性Slc 30 a10或Slc 39 a14敲除小鼠（SLC 30 A10和SLC 39 A14是Mn转运蛋白）的分析表明，在生理条件下：1）肝脏和肠道的Mn排泄是调节脑Mn的主要途径;令人惊讶的是，2）肠道补偿了肝脏Mn排泄在控制脑Mn中的损失。肠道在控制生理脑锰的意想不到的重要性，使我们确定的作用，肝脏和肠道锰排泄在调节脑锰在锰暴露升高。我们使用肝脏或精氨酸特异性Slc 30 a10基因敲除小鼠作为模型，以抑制肝脏或肠道锰排泄。与同窝仔相比，这两个基因敲除菌株表现出类似的增加，在早期或后期生活中锰暴露升高后，脑锰。因此，与生理条件不同，在锰暴露升高期间，需要肝脏和肠道锰排泄来控制脑锰。然而，大脑锰水平的同窝出生的和两个基因敲除株暴露于高锰只在生命早期正常化，在以后的生活。因此，肝脏和肠道锰排泄在清除早期锰暴露积累的脑锰中起代偿作用。最后，神经运动试验提供的证据与肝脏和肠道锰排泄在功能调节锰神经毒性锰暴露过程中的作用一致。总而言之，这些发现大大提高了对大脑锰的调节排泄的理解。新&值得注意的是，本文表明，与预期从以前的研究和生理条件相比，由肠道和肝脏的锰排泄是同样重要的控制脑锰在人类相关的锰暴露。这些结果为在生物体水平上控制脑锰稳态的器官间机制提供了基础性见解，并对开发治疗锰诱导的神经系统疾病的疗法具有重要意义。https://ajpgi.podbean.com/e/got-guts-the-micro-version-with-steven-hutchens-and-somshuvra-mukhopadhyay
Manganese (Mn) is essential but neurotoxic at elevated levels. Under physiological conditions, Mn is primarily excreted by the liver, with the intestines playing a secondary role. Recent analyses of tissue-specificSlc30a10orSlc39a14knockout mice (SLC30A10 and SLC39A14 are Mn transporters) revealed that, under physiological conditions:1) excretion of Mn by the liver and intestines is a major pathway that regulates brain Mn; and surprisingly,2) the intestines compensate for loss of hepatic Mn excretion in controlling brain Mn. The unexpected importance of the intestines in controlling physiological brain Mn led us to determine the role of hepatic and intestinal Mn excretion in regulating brain Mn during elevated Mn exposure. We used liver- or intestine-specificSlc30a10knockout mice as models to inhibit hepatic or intestinal Mn excretion. Compared with littermates, both knockout strains exhibited similar increases in brain Mn after elevated Mn exposure in early or later life. Thus, unlike physiological conditions, both hepatic and intestinal Mn excretion are required to control brain Mn during elevated Mn exposure. However, brain Mn levels of littermates and both knockout strains exposed to elevated Mn only in early life were normalized in later life. Thus, hepatic and intestinal Mn excretion play compensatory roles in clearing brain Mn accumulated by early life Mn exposure. Finally, neuromotor assays provided evidence consistent with a role for hepatic and intestinal Mn excretion in functionally modulating Mn neurotoxicity during Mn exposure. Put together, these findings substantially enhance understanding of the regulation of brain Mn by excretion.NEW & NOTEWORTHYThis article shows that, in contrast with expectations from prior studies and physiological conditions, excretion of manganese by the intestines and liver is equally important in controlling brain manganese during human-relevant manganese exposure. The results provide foundational insights about the interorgan mechanisms that control brain manganese homeostasis at the organism level and have important implications for the development of therapeutics to treat manganese-induced neurological disease.Listen to this article’s corresponding podcast at https://ajpgi.podbean.com/e/got-guts-the-micro-version-with-steven-hutchens-and-somshuvra-mukhopadhyay.