John Cochran VA Medical Center, St. Louis, Missouri, USA.
Center for Cardiovascular Research and Division of Cardiology in Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Compr Physiol. 2018 Sep 14;8(4):1639-1667. doi: 10.1002/cphy.c180005.
Adaptive responses that counter starvation have evolved over millennia to permit organismal survival, including changes at the level of individual organelles, cells, tissues, and organ systems. In the past century, a shift has occurred away from disease caused by insufficient nutrient supply toward overnutrition, leading to obesity and diabetes, atherosclerosis, and cardiometabolic disease. The burden of these diseases has spurred interest in fasting strategies that harness physiological responses to starvation, thus limiting tissue injury during metabolic stress. Insights gained from animal and human studies suggest that intermittent fasting and chronic caloric restriction extend lifespan, decrease risk factors for cardiometabolic and inflammatory disease, limit tissue injury during myocardial stress, and activate a cardioprotective metabolic program. Acute fasting activates autophagy, an intricately orchestrated lysosomal degradative process that sequesters cellular constituents for degradation, and is critical for cardiac homeostasis during fasting. Lysosomes are dynamic cellular organelles that function as incinerators to permit autophagy, as well as degradation of extracellular material internalized by endocytosis, macropinocytosis, and phagocytosis. The last decade has witnessed an explosion of knowledge that has shaped our understanding of lysosomes as central regulators of cellular metabolism and the fasting response. Intriguingly, lysosomes also store nutrients for release during starvation; and function as a nutrient sensing organelle to couple activation of mammalian target of rapamycin to nutrient availability. This article reviews the evidence for how the lysosome, in the guise of a janitor, may be the "undercover boss" directing cellular processes for beneficial effects of intermittent fasting and restoring homeostasis during feast and famine. © 2018 American Physiological Society. Compr Physiol 8:1639-1667, 2018.
适应饥饿的反应在数千年的时间里不断进化，以允许生物生存，包括个体细胞器、细胞、组织和器官系统水平的变化。在过去的一个世纪里，人们的饮食结构发生了从营养供应不足导致疾病向营养过剩导致肥胖和糖尿病、动脉粥样硬化和心脏代谢疾病的转变。这些疾病的负担促使人们对利用饥饿生理反应的禁食策略产生了兴趣，从而限制代谢应激时的组织损伤。动物和人类研究的结果表明，间歇性禁食和慢性热量限制可以延长寿命，降低心脏代谢和炎症性疾病的风险因素，限制心肌应激时的组织损伤，并激活心脏保护性代谢程序。急性禁食会激活自噬，这是一种错综复杂的溶酶体降解过程，它会将细胞成分隔离起来进行降解，这对禁食期间的心脏稳态至关重要。溶酶体是动态的细胞细胞器，作为自噬的焚烧炉，以及通过胞吞作用、巨胞饮作用和吞噬作用内化的细胞外物质的降解，发挥作用。在过去的十年中，人们对溶酶体作为细胞代谢和禁食反应的中央调节者的认识有了突飞猛进的发展。有趣的是，溶酶体还储存营养物质，以备饥饿时释放；作为一种营养感应细胞器，它可以将哺乳动物雷帕霉素靶蛋白的激活与营养供应联系起来。本文综述了溶酶体作为“幕后老板”，通过自噬作用来指导细胞过程，从而实现间歇性禁食的有益效果，并在饱食和饥饿时恢复体内平衡的证据。 2018 年美国生理学会。综合生理学 8:1639-1667,2018。
