A liver-specific mitochondrial carrier that controls gluconeogenesis and energy expenditure
A liver-specific mitochondrial carrier that controls gluconeogenesis and energy expenditure
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DOI：
10.1101/2022.12.06.519308
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发表时间：
2022-12
期刊：
影响因子：
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通讯作者：
Jin-Seon Yook;Zachary H Taxin;Bo Yuan;Satoshi Oikawa;C. Auger;B. Mutlu;P. Puigserver;Sheng Hui
中科院分区：
文献类型：
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作者：
Jin-Seon Yook;Zachary H Taxin;Bo Yuan;Satoshi Oikawa;C. Auger;B. Mutlu;P. Puigserver;Sheng Hui
线粒体为能量稳态的调节提供必需的代谢物和 ATP。例如，在禁食状态下，肝线粒体是糖异生前体的重要来源。然而，线粒体膜运输水平的调节机制尚不完全清楚。在这里，我们报告了一种肝脏特异性线粒体内膜载体 SLC25A47，它是肝脏糖异生和能量稳态所必需的。全基因组关联研究发现 SLC25A47 与人类空腹血糖、HbA1c 和胆固醇水平之间存在显着关联。在小鼠中，我们证明 Slc25a47 的肝脏特异性缺失选择性地损害了乳酸的肝脏糖异生，同时显着增强了全身能量消耗和 FGF21 的肝脏表达。这些代谢变化并不是一般肝功能障碍的结果，因为成年小鼠的急性 SLC25A47 缺失足以增强肝脏 FGF21 的产生、丙酮酸耐受性和胰岛素耐受性，而与肝损伤和线粒体功能障碍无关。从机制上讲，SLC25A47 缺失会导致肝脏丙酮酸通量受损和苹果酸在线粒体中积累，从而限制肝脏糖异生。总之，本研究确定了线粒体内膜中的一个关键节点，该节点调节禁食诱导的糖异生和能量稳态。意义 鉴于线粒体内膜具有不可穿透的性质，大多数已知的代谢物载体蛋白（包括 SLC25A 家族成员）在哺乳动物组织中普遍表达。一个例外是 SLC25A47，它选择性地在肝脏中表达。目前的研究表明，SLC25A47 的消耗会减少禁食状态下线粒体丙酮酸通量和肝脏糖异生，同时激活能量消耗。目前的工作提供了一个肝脏特异性靶标，通过它我们可以限制肝脏糖异生，在高血糖和糖尿病条件下，肝脏糖异生通常会过量。
Mitochondria provide essential metabolites and ATP for the regulation of energy homeostasis. For instance, liver mitochondria are a vital source of gluconeogenic precursors under a fasted state. However, the regulatory mechanisms at the level of mitochondrial membrane transport are not fully understood. Here, we report a liver-specific mitochondrial inner-membrane carrier, SLC25A47, which is required for hepatic gluconeogenesis and energy homeostasis. Genome-wide association studies found significant associations between SLC25A47 and fasting glucose, HbA1c, and cholesterol levels in humans. In mice, we demonstrated that liver-specific deletion of Slc25a47 impaired hepatic gluconeogenesis selectively from lactate, while significantly enhancing whole-body energy expenditure and the hepatic expression of FGF21. These metabolic changes were not a consequence of general liver dysfunction because acute SLC25A47 deletion in adult mice was sufficient to enhance hepatic FGF21 production, pyruvate tolerance, and insulin tolerance independent of liver damage and mitochondrial dysfunction. Mechanistically, SLC25A47 loss leads to impaired hepatic pyruvate flux and malate accumulation in the mitochondria, thereby restricting hepatic gluconeogenesis. Together, the present study identified a crucial node in the mitochondrial inner-membrane that regulates fasting-induced gluconeogenesis and energy homeostasis. SIGNIFICANCE Given the impenetrable nature of the mitochondrial inner-membrane, most of the known metabolite carrier proteins, including SLC25A family members, are ubiquitously expressed in mammalian tissues. One exception is SLC25A47 which is selectively expressed in the liver. The present study showed that depletion of SLC25A47 reduced mitochondrial pyruvate flux and hepatic gluconeogenesis under a fasted state, while activating energy expenditure. The present work offers a liver-specific target through which we can restrict hepatic gluconeogenesis, which is often in excess under hyperglycemic and diabetic conditions.