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.
Cell Metab. 2019 Jun 4;29(6):1291-1305.e8. doi: 10.1016/j.cmet.2019.03.014. Epub 2019 Apr 18.
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.
肝脏的 TCA 循环支持氧化和生物合成代谢。这种双重责任需要像丙酮酸羧化酶（PC）这样的补充途径来生成 TCA 循环中间产物，以支持生物合成而不破坏氧化代谢。为了测试补充通量在肝脏代谢中的作用，创建了肝脏特异性 PC 敲除（LPCKO）小鼠。LPCKO 小鼠的肝脏补充作用受损，TCA 循环中间产物减少，糖异生受到抑制，TCA 循环通量减少，酮生成和肾脏糖异生代偿性增加。PC 的缺失耗尽了天冬氨酸并损害了尿素循环功能，导致尿素循环中间产物升高和高氨血症。PC 的缺失阻止了饮食诱导的高血糖和胰岛素抵抗，但耗尽了 NADPH 和谷胱甘肽，这加剧了氧化应激，并与升高的肝炎症相关。因此，尽管 PC 催化了其他补充途径也产生的中间产物的合成，但它对于维持氧化、生物合成以及 TCA 循环以外的途径（如抗氧化防御）是特异性必需的。
