Autophagy and regulation of lipid metabolism

Abstract

Macroautophagy (henceforth referred to as autophagy) is an in-bulk lysosomal degradative pathway that plays a crucial role in the maintenance of cellular homeostasis through the removal of damaged proteins and aged organelles. Following nutrient deprivation, a primary cellular response is the induction of autophagy that breaks down redundant cellular components and provides amino acids and additional precursor molecules for processes critical for cellular survival. In parallel, nutrient depletion leads to the mobilization of cellular lipid stores to supply free fatty acids for energy, thus pointing to regulatory and functional similarities between autophagy and lipid metabolism. The current chapter discusses the novel and mutually exclusive roles of autophagy in the regulation of lipid metabolism in the liver and of fat storage within the adipose tissue. Our studies in cultured hepatocytes and the murine liver have demonstrated that autophagy serves to degrade intracellular lipid stores through a process that we have termed "macrolipophagy" and that ablation of liver-specific autophagy leads to excessive hepatic lipid accumulation and the development of fatty liver. In contrast, preadipocytes in culture that lacked autophagy failed to differentiate into mature adipocytes and exhibited a reduction in fat storage that translated to decreased adipose tissue mass in an in vivo mouse model. These recent findings establish an association between autophagy and regulation of hepatic lipid metabolism and adipose tissue biology, thus providing new mechanistic insights into the regulation of these complex processes. These findings also highlight the possibility of novel therapeutic approaches, such as differential organ-specific regulation of autophagy to solve problems that arise from lipid over accumulation that occur in the metabolic syndrome and with aging.

Fig. 1

Types of autophagy in mammalian cells. Three types of autophagy have been described in mammalian cells, macroautophagy, an in-bulk degradative pathway that requires the de novo synthesis of a limiting membrane for sequestration and delivery of cargo to the lysosome. Microautophagy involves engulfment of cytosolic material by the lysosomal membrane itself. Chaperone-mediated autophagy targets specific proteins containing the recognition template, KFERQ motif to lysosomal membrane-associated translocation complex, LAMP-2A, for substrate internalization and degradation

Fig. 2

Autophagy induction complex (a) and (b) conjugation cascades that lead to autophagosome formation. The induction of autophagy requires release of Beclin-1 from Bcl-2 and its binding to vps15, vps30, vps34, and UVRAG to form the active Class III PI3K complex. Lipid phosphorylation by active class III PI3K recruits the two conjugation cascades to the site of autophagosome formation. The LC3 and ATG5–12 conjugation cascades require the ubiquitin-like ligase activity of ATG7. Products of these two cascades, LC3-II and the ATG5–12–16 conjugate, form structural components of the limiting membrane

Fig. 3

The process of macrolipophagy occurs by the de novo formation of a limiting membrane that sequesters cytosolic lipid droplets and delivers the lipid cargo to the lysosomes for degradation