ABSTRACT
Many cells are able to degrade intracellular proteins by macroautophagy.1'3 In this multistep process, regions of cytoplasm are surrounded by a double membrane to form an organelle called an early autophagosome.1,4 The material sequestered in such autophagosomes includes recognizable organelles such as mitochondria, peroxisomes, ribosomes, and glycogen granules, as well as a variety of cytosolic proteins in proportion to their abundance in the cytosol (Table 4.1).5,6 Large cytoskeletal elements as well as nuclear structures are excluded from autophagosomes.1'3
The origin of the two membranes that surround the autophagosome remains uncertain despite extensive studies over the past 30 years.1'3,7'9 The autophagosome then acquires the membrane ATP-dependent proton pump, as well as certain other lysosomal mem brane proteins within its outer-membrane, and becomes acidic.1'3 These structures still contain two membranes and are called late autophagosomes.1,4 The early and late autophagosomes together are also referred to as autophagic vacuoles. The late autophagosomes then acquire lysosomal hydrolases and additional lysosomal membrane proteins by fusion with primary or secondary lysosomes.1'3 Simultaneously, the innermembrane of the late autophagosome is digested to form a structure called an autolysosome.1,4 The autolysosome is more acidified than the late autophagosome, and in the autolysosome the contents of the autophagic vacuole are digested (Fig. 4.1). Each of these steps in macroautophagy requires ATP.1'3
Rates of macroautophagy in liver are regulated by amino acids and hormones.1-3 In the perfused rat liver leucine is an especially potent regulator of macroautophagy, but seven additional amino acids are required for maximal suppression of macroautophagy.2,10,11 Insulin inhibits while glucagon stimulates macroautophagy.1,3,10,11 These considerations explain why macroautophagy is stimulated in liver between meals when circulating amino acid levels fall and the insulin/glucagon ratio is low.
