Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver.,Cell Metabolism

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Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver.
Cell Metabolism ( IF 27.7 ) Pub Date : 2019-04-18 , DOI: 10.1016/j.cmet.2019.03.014
David A Cappel ₁ , Stanisław Deja ₂ , João A G Duarte ₃ , Blanka Kucejova ₁ , Melissa Iñigo ₁ , Justin A Fletcher ₁ , Xiaorong Fu ₁ , Eric D Berglund ₄ , Tiemin Liu ₅ , Joel K Elmquist ₆ , Suntrea Hammer ₇ , Prashant Mishra ₈ , Jeffrey D Browning ₉ , Shawn C Burgess ₁₀

Affiliation

Center for Human Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Center for Human Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Center for Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Sate Key Laboratory of Genetic Engineering, School of Life Sciences, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, Shanghai 200438, China.
Center for Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Clinical Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Center for Human Nutrition, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.

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.

中文翻译：

丙酮酸羧化酶介导的动脉粥样硬化通过维持TCA循环和肝脏中的氧化还原代谢来促进抗氧化能力。

肝TCA循环支持氧化和生物合成代谢。这种双重责任需要诸如丙酮酸羧化酶（PC）的抗衰老途径，以生成生物合成必需的TCA循环中间体，而不会破坏氧化代谢。创建了肝脏特异性PC基因敲除（LPCKO）小鼠，以测试动脉粥样硬化通量在肝脏代谢中的作用。LPCKO小鼠肝功能不全受损，TCA循环中间体减少，糖异生抑制，TCA循环通量减少，生酮和肾糖异生的代偿性增加。PC的损失会耗尽天冬氨酸并损害尿素循环功能，从而导致尿素循环中间体和高氨血症升高。PC的损失阻止了饮食引起的高血糖和胰岛素抵抗，但耗尽了NADPH和谷胱甘肽，会加剧氧化应激，并与肝脏发炎相关。因此，尽管催化了也由其他过继反应途径产生的中间体的合成，但是PC对于维持氧化，生物合成和TCA循环远端的途径，例如抗氧化剂防御特别地是必需的。

更新日期：2019-05-16

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