Autophagy in nonalcoholic steatohepatitis - PubMed (original) (raw)
Review
Autophagy in nonalcoholic steatohepatitis
Muhammad Amir et al. Expert Rev Gastroenterol Hepatol. 2011 Apr.
Abstract
Autophagy is a critical pathway for the degradation of intracellular components by lysosomes. Established functions for both macroautophagy and chaperone-mediated autophagy in hepatic lipid metabolism, insulin sensitivity and cellular injury suggest a number of potential mechanistic roles for autophagy in nonalcoholic steatohepatitis (NASH). Decreased autophagic function in particular may promote the initial development of hepatic steatosis and progression of steatosis to liver injury. Additional functions of autophagy in immune responses and carcinogenesis may also contribute to the development of NASH and its complications. The impairment in autophagy that occurs with cellular lipid accumulation, obesity and aging may therefore have an important impact on this disease, and agents to augment hepatic autophagy have therapeutic potential in NASH.
Conflict of interest statement
Financial & competing interests disclosure
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Figures
Figure 1. The three types of autophagy
In macroautophagy, a double membrane of unclear origin begins to form a phagophore around cytosolic components, such as mitochondria, lipid droplets and proteins. These cellular elements become completely enclosed within an autophagosome, which translocates to a lysosome full of hydrolases. Fusion of these two structures into an autophagolysosome leads to the enzymatic degradation of the cellular components. In chaperone-mediated autophagy, cytosolic proteins containing a pentapeptide motif bind to the chaperone Hsc70. This complex binds to the LAMP-2A receptor on the lysosome for internalization and degradation. Microautophagy involves the uptake of cellular components within an invagination of the lysosomal membrane for enzymatic degradation. LAMP-2A: Lysosome-associated membrane protein type 2A.
Figure 2. Inter-relationships among cellular changes in lipid content or insulin sensitivity and levels of macroautophagy
In nonalcoholic fatty liver disease, both steatosis and hyperinsulinemia may act to inhibit levels of macroautophagy. Cellular lipid accumulation can inhibit macroautophagy by impeding the fusion of autophagosomes to lysosomes. The mechanism of the inhibitory effect of hyperinsulinemia on autophagy may be through decreased activation of FOXO1. The resultant reduction in macroautophagy may then accelerate steatosis by impairing lipolytic breakdown of lipids stored in lipid droplets. The decrease in macroautophagy may also exacerbate insulin resistance by causing increased ER stress, which worsens hepatic insulin resistance. ER: Endoplasmic reticulum.
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