ReviewAMPK and autophagy in glucose/glycogen metabolism
Introduction
As a primary energy source, glucose places on central blocks of metabolism in the whole body. Glucose falls into a Krebs cycle not only to produce energy by oxidative phosphorylation but also to provide biosynthetic intermediates for fatty acid, amino acid, and nucleotides, depending on cellular needs. Also, it is stored as glycogen, essentially in liver and muscles. Importantly, the metabolic regulation of glucose/glycogen is quite different between tissues, for example, liver (to maintain blood glucose level) and muscle (to provide cellular energy). Therefore, glucose metabolism is tightly regulated, and it includes the multiple layers of molecular networks for many different metabolic results between tissues. Many lines of evidence have identified a variety of signaling molecules to regulate glucose/glycogen metabolism in response to distinct metabolic stress. Among them, AMP-activated protein kinase (AMPK) has been extensively demonstrated as an important metabolic regulator functioning on various metabolic stresses, in which AMPK inhibits anabolic pathway and simultaneously activates catabolic pathway for energy homeostasis. Interestingly, accumulating reports have shown that lysosomal-dependent catabolic program, autophagy, plays important roles in macromolecular nutrient degradation, such as glycogen and lipid droplets. In addition to canonical degradation of glycogen by glycogen phosphorylase, autophagy-dependent glycogen degradation is reported as an important glucose-supplying alternative like gluconeogenesis. The accumulating lines of evidence showing the interplay between autophagy and carbohydrate metabolism reveal the existence of a dynamic feedback between autophagy and cellular energy balance. The recent advances on the molecular machinery on autophagy have allowed studying the molecular basis underlying the functional interaction between autophagy and cellular metabolism. Furthermore, much effort has revealed that a number of nutrient signaling molecules, including AMPK, are involved in the regulation of autophagy. Here, we discuss the regulation between AMPK, autophagy, and glucose/glycogen metabolism, as well as the alterations of such control in the metabolic disorders.
Section snippets
AMP-activated protein kinase (AMPK)
Glucose uptake and glycogen synthesis in skeletal muscle are closely linked processes that require recruitment of glucose transport 4 (GLUT4) to the cell surface and activation of glycogen synthase, respectively. These processes are sophisticatedly regulated by insulin, but muscle contraction also promotes glucose uptake and regulates glycogen synthesis in a manner independent of insulin. Elucidation of insulin-independent mechanisms for these processes is of great therapeutic interest for
Autophagy as an alternative metabolic pathway
Autophagy is an important catabolic program to handle a variety of macromolecular cellular contents, ranging from protein aggregates, dysfunctional subcellular organelles, infected pathogens, to the storage nutrients (glycogen and lipid droplets), in order to maintain cellular homeostasis (Boya et al, 2013, Cuervo, Macian, 2012, Kaushik et al, 2010, Singh, Cuervo, 2011, Sridhar et al, 2012). Autophagy degrades these cytoplasmic components by delivering them into the lysosomes (or vacuoles in
Concluding remarks
Glucose/glycogen metabolism is a primary cell metabolism balancing cellular energy in response to a variety of environmental cues. Therefore, the metabolic regulation of glucose/glycogen occurs differently to meet the distinct cellular needs and multiple layers of regulatory circuits should cooperate to maintain cell homeostasis in the whole body. Many lines of evidence have indicated that AMPK plays an important role in these carbohydrate metabolisms. Also, a growing body of evidence have shed
Acknowledgement
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST, No. 2011-0030072 to J. Ha; No. 2012R1A5A2051387 to J. Kim), and by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MEST) (No. 2012M3A9C6049935 to J. Kim), respectively.
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