The mitochondrial dicarboxylate carrier mediates in vivo hepatic gluconeogenesis

bioRxiv - Biochemistry Pub Date : 2024-09-13 DOI:10.1101/2024.09.12.612761

Daniel J Pape, Kelly C Falls-Hubert, Ronald A Merrill, Adnan Ahmed, Qingwen Qian, Gavin R McGivney, Paulina Sobieralski, Adam J Rauckhorst, Ling Yang, Eric B Taylor

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Abstract

Hepatic gluconeogenesis (GNG) is essential for maintaining euglycemia during prolonged fasting. However, GNG becomes pathologically elevated and drives chronic hyperglycemia in type 2 diabetes (T2D). Lactate/pyruvate is a major GNG substrate known to be imported into mitochondria for GNG. Yet, the subsequent mitochondrial carbon export mechanisms required to supply the extra-mitochondrial canonical GNG pathway have not been genetically delineated. Here, we evaluated the role of the mitochondrial dicarboxylate carrier (DiC) in mediating GNG from lactate/pyruvate. We generated liver-specific DiC knockout (DiC LivKO) mice. During lactate/pyruvate tolerance tests, DiC LivKO decreased plasma glucose excursion and ¹³C-lactate/-pyruvate flux into hepatic and plasma glucose. In a Western diet (WD) feeding model of T2D, acute DiC LivKO after induction of obesity decreased lactate/pyruvate-driven GNG, hyperglycemia, and hyperinsulinemia. Our results show that mitochondrial carbon export through the DiC mediates GNG and that the DiC contributes to impaired glucose homeostasis in a mouse model of T2D.

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线粒体二羧酸载体介导体内肝糖生成

肝糖原生成（GNG）对于在长期禁食期间维持优血症至关重要。然而，在 2 型糖尿病（T2D）中，GNG 会病理性升高，并导致慢性高血糖。已知乳酸/丙酮酸是一种主要的 GNG 底物，可输入线粒体用于 GNG。然而，供应线粒体外典型 GNG 途径所需的后续线粒体碳输出机制尚未从遗传学角度加以界定。在这里，我们评估了线粒体二羧酸盐载体（DiC）在介导乳酸/丙酮酸的 GNG 中的作用。我们培育了肝脏特异性 DiC 基因敲除（DiC LivKO）小鼠。在乳酸/丙酮酸耐受性试验中，DiC LivKO降低了血浆葡萄糖的偏移和13C-乳酸/丙酮酸进入肝脏和血浆葡萄糖的通量。在西方饮食（WD）喂养的 T2D 模型中，诱导肥胖后的急性 DiC LivKO 可减少乳酸/丙酮酸驱动的 GNG、高血糖和高胰岛素血症。我们的研究结果表明，线粒体碳输出通过 DiC 介导了 GNG，而 DiC 在 T2D 小鼠模型中导致了葡萄糖稳态受损。

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bioRxiv - Biochemistry

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