Regulation of Liver Metabolism by Autophagy - PubMed (original) (raw)
Review
Regulation of Liver Metabolism by Autophagy
Julio Madrigal-Matute et al. Gastroenterology. 2016 Feb.
Abstract
Intracellular components must be recycled for cells to maintain energy and ensure quality control of proteins and organelles. Autophagy is a highly conserved recycling process that involves degradation of cellular constituents in lysosomes. Although autophagy regulates a number of cell functions, it was first found to maintain energy balance in liver cells. As our understanding of autophagy has increased, we have found its connections to energy regulation in liver cells to be tight and complex. We review 3 mechanisms by which hepatic autophagy monitors and regulates cellular metabolism. Autophagy provides essential components (amino acids, lipids, and carbohydrates) required to meet the cell's energy needs, and it also regulates energy supply by controlling the number, quality, and dynamics of the mitochondria. Finally, autophagy also modulates levels of enzymes in metabolic pathways. In light of the multiple ways in which autophagy participates to control liver metabolism, it is no surprise that dysregulation of autophagy has been associated with metabolic diseases such as obesity, diabetes, or metabolic syndrome, as well as liver-specific disorders such as fatty liver, nonalcoholic steatohepatitis, and hepatocellular carcinoma. We discuss some of these connections and how hepatic autophagy might serve as a therapeutic target in common metabolic disorders.
Keywords: Cancer; Chaperone-Mediated Autophagy; Lipophagy; Lysosome; Macroautophagy.
Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
DISCLOSURE: The authors have no conflict of interest.
Figures
Figure 1. Scheme of autophagy pathways in the liver
Schematic depiction of the three types of autophagy that coexist in liver.
Macroautophagy
is (A) initiated with the formation of the limiting membrane using lipids and proteins from different organelles. Cargo sequestration (B) can occur in bulk or in a selective manner mediated by soluble protein receptors. After engulfment (C) the sealed vesicle (autophagosome) traffics (D) via microtubules and delivers cargo to lysosomes through membrane fusion (E) to form an autolysosome where cargo is degraded by lysosomal hydrolases (F).
In chaperone-mediated autophagy
(CMA), all substrates carry a pentapeptide (KFERQ-like) recognized (A) by the cytosolic chaperone Hsc70. The substrate-chaperone complex binds (B) to the CMA receptor LAMP-2A at the lysosomal membrane. The substrate must be unfolded (C) before translocation (D) through the multimeric complex formed by LAMP-2A at the lysosomal membrane. A luminal Hsc70 assists in substrate translocation into lysosome where the substrate is finally degraded (E).
Microautophagy
in liver has been observed in late endosomes where proteins also carrying KFERQ-like motifs are internalized in small microvesicles that form through invagination of the endosomal membrane. As in CMA, the consensus motif allows Hsc70 recognition (A), but in this case the substrate/chaperone complex binds directly to lipids at the endosomal membrane (B). Microvesicles trapping this cargo that form in an ESCRT-dependent manner are internalized (C) into the endosome lumen where degradation takes place (D). Some degradation may also be completed upon endosome/lysosomal fusion. In the case of yeast, direct trapping of lipid droplets by the vacuole (yeast lysosome equivalent) through a microautophagy-like process has been described, but whether or not this process also takes place in mammalian lysosomes requires future investigation.
Figure 2. Three main functions of hepatic autophagy in the control of the energetic balance
A: Autophagy recycles essential components through degradation of cellular proteins and energy stores. The type of cargo selected by autophagy, at least in liver, changes depending on the duration of nutrient scarcity. While in bulk autophagy of cytosolic proteins and organelles is predominant early in starvation and constitutes an important source of amino acids, if nutrients shortage persists, there is a switch toward glycogen and lipid droplets as preferential cargos. Glycophagy and lipohagy contribute thus glucose and free fatty acids that can be utilized to sustain a positive energetic balance in absence of nutrients. B: Autophagy also manages the cellular energetic balance through the fine-tuned regulation of mitocondrial number and quality control. Mitophagy can eliminate non-functional mitochondria but also controls mitochondrial mass through a coordinated balance with mitochondrial biogenesis. C: Autophagy contributes to accommodation to starvation and other nutritional challenges through selective removal via chaperone-mediated autophagy (CMA) of enzymes that control metabolic pathways such as glycolysis or lipogenesis. In addition, CMA also regulates hepatic lipolytic capacity through degradation of perilipins in the surface of lipid droplets. Removal of these proteins is necessary for cytosolic lipases and autophagy factors to gain access to the lipids in the core of the lipid droplets.
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References
- Mizushima N. The pleiotropic role of autophagy: from protein metabolism to bactericide. Cell Death Differ. 2005;12:1535–1541. - PubMed
- Kuma A, Hatano M, Matsui M, et al. The role of autophagy during the early neonatal starvation period. Nature. 2004;432:1032–1036. - PubMed
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