Mammalian autophagy is essential for hepatic and renal ketogenesis during starvation.
Mammalian autophagy is essential for hepatic and renal ketogenesis during starvation.
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DOI：
10.1038/srep18944
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发表时间：
2016-01-06
影响因子：
4.6
通讯作者：
Uzu T
中科院分区：
文献类型：
--
作者：
Takagi A;Kume S;Kondo M;Nakazawa J;Chin-Kanasaki M;Araki H;Araki S;Koya D;Haneda M;Chano T;Matsusaka T;Nagao K;Adachi Y;Chan L;Maegawa H;Uzu T
自噬是一种跨物种的细胞内降解系统，由饥饿激活。虽然越来越多的证据表明哺乳动物自噬参与了一些现代疾病的发病机制，但其在对抗饥饿中的生理作用尚未完全阐明。在这项研究中，我们分析了在肝脏，骨骼肌或肾脏缺乏自噬的小鼠品系中饥饿诱导的胚胎发生和生酮。任何组织中的自噬缺陷在饥饿期间对同源性没有影响。虽然骨骼肌和肾脏特异性自噬缺陷没有改变饥饿诱导的血酮水平增加，但肝脏特异性自噬缺陷显著减弱了这种影响。有趣的是，肾脏以及肝脏的HMG-CoA合成酶2的表达增加与长期饥饿。此外，在饥饿期间，肝脏和肾脏都缺乏自噬的小鼠比仅在肝脏缺乏自噬的小鼠表现出更低的血酮水平和体力活动。饥饿诱导大量的脂肪外组织，包括肝脏和肾脏，这是必要的生酮形成的脂滴。此外，这一过程在自噬缺陷的肝脏和肾脏中受损。这些研究结果表明，肝和肾的自噬是必不可少的饥饿诱导的脂滴形成和随后的生酮，并最终维持全身能量稳态。我们的发现为哺乳动物对抗饥饿的适应机制提供了新的生物学见解。
Autophagy is an intracellular degradation system activated, across species, by starvation. Although accumulating evidence has shown that mammalian autophagy is involved in pathogenesis of several modern diseases, its physiological role to combat starvation has not been fully clarified. In this study, we analysed starvation-induced gluconeogenesis and ketogenesis in mouse strains lacking autophagy in liver, skeletal muscle or kidney. Autophagy-deficiency in any tissue had no effect on gluconeogenesis during starvation. Though skeletal muscle- and kidney-specific autophagy-deficiency did not alter starvation-induced increases in blood ketone levels, liver-specific autophagy-deficiency significantly attenuated this effect. Interestingly, renal as well as hepatic expression of HMG-CoA synthase 2 increased with prolonged starvation. Furthermore, during starvation, mice lacking autophagy both in liver and kidney showed even lower blood ketone levels and physical activity than mice lacking autophagy only in liver. Starvation induced massive lipid droplet formation in extra-adipose tissues including liver and kidney, which was essential for ketogenesis. Moreover, this process was impaired in the autophagy-deficient liver and kidney. These findings demonstrate that hepatic and renal autophagy are essential for starvation-induced lipid droplet formation and subsequent ketogenesis and, ultimately, for maintaining systemic energy homeostasis. Our findings provide novel biological insights into adaptive mechanisms to combat starvation in mammals.