美国德克萨斯大学西南医学中心的Shawn C. Burgess研究组，发现丙酮酸羧化酶介导的回补通过维持三羧酸循环以及氧化还原代谢来促进肝脏的抗氧化能力。这一研究成果发表在2019年6月出版的国际学术期刊《Cell Metabolism》上。

为揭示回补通路在肝脏代谢中的功能，研究人员构建了肝脏特异性敲除丙酮酸羧化酶（LPCKO）的小鼠。这些小鼠表现出肝回补受损、三羧酸循环中间产物减少、糖异生受阻、三羧酸循环流降低以及代偿性酮体生成和肾糖异生增加的表型。丙酮酸羧化酶的缺失使得天冬氨酸枯竭以及尿素循环功能受损，进而引起尿素循环的中间产物增加以及高氨血症。此外，丙酮酸羧化酶的缺失防止了饮食引起的高血糖症和胰岛素抵抗，但也因为耗尽NADPH和谷胱甘肽促进了氧化应激和肝脏炎症。因此，这项工作表明，尽管丙酮酸羧化酶催化产生的中间产物是其他回补通路也能够产生的，但其在维持氧化平衡、生物合成以及像抗氧化防御这样离三羧酸循环还比较远的通路中都具有极为必要的贡献。

据介绍，肝脏三羧酸循环为氧化和生物合成代谢提供支持。这双重的功能需要例如丙酮酸羧化酶这样的回补通路来生成三羧酸循环里的中间产物，从而在用于生物合成的同时不扰乱氧化代谢。

附：英文原文

Title: Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver

Author: David A. Cappel, Prashant Mishra, Jeffrey D. Browning, Shawn C. Burgess

Issue&Volume: Jun 04, 2019 Volume 29Issue 6

Abstract: The hepatic TCA cycle supports oxidative and biosynthetic metabolism. This dual responsibility requires anaplerotic pathways, such as pyruvate carboxylase (PC), to generate TCA cycle intermediates necessary for biosynthesis without disrupting oxidative metabolism. Liver-specific PC knockout (LPCKO) mice were created to test the role of anaplerotic flux in liver metabolism. LPCKO mice have impaired hepatic anaplerosis, diminution of TCA cycle intermediates, suppressed gluconeogenesis, reduced TCA cycle flux, and a compensatory increase in ketogenesis and renal gluconeogenesis. Loss of PC depleted aspartate and compromised urea cycle function, causing elevated urea cycle intermediates and hyperammonemia. Loss of PC prevented diet-induced hyperglycemia and insulin resistance but depleted NADPH and glutathione, which exacerbated oxidative stress and correlated with elevated liver inflammation. Thus, despite catalyzing the synthesis of intermediates also produced by other anaplerotic pathways, PC is specifically necessary for maintaining oxidation, biosynthesis, and pathways distal to the TCA cycle, such as antioxidant defenses.

DOI: https://doi.org/10.1016/j.cmet.2019.03.014

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30184-6