Capitalizing on the Autophagic Response for Treatment of Liver Disease Caused by Alpha-1-Antitrypsin Deficiency and Other Genetic Diseases
Figure 2
Regulation of autophagy and possible targets of the autophagy enhancer drugs. Drugs that modulate autophagy can be divided into two categories depending on whether or not they act through mTOR, a master negative regulator of autophagy that functions through the formation of mTORC1 complex. This complex is suppressed by specific inhibitors such as rapamycin and its analogs, which therefore enhance autophagy [43]. A recent study showed that ezetimibe perturbed the cholesterol homeostasis and decreased mTOR recruitment to late endosome/lysosome; thus ezetimibe is thought to induce autophagy by suppressing mTORC1 [28]. The mTOR signaling pathway can also be regulated by specific inhibitors target to the upstream of mTOR, for example, PI3K inhibitor [44]. In addition, nuclear translocation of TFEB promoted autophagic degradation of ATZ in PiZ mouse model [33]. There is evidence showing that TFEB interacts with mTORC1 on the lysosomal membrane; because it promotes phosphorylation of TFEB, mTORC1 is now considered an antagonist of TFEB activity [32]. Tat-beclin 1 peptide is identified as a potent inducer of autophagy and enhances the degradation of mutant huntingtin and several invasive bacterial and viral pathogens [30]. Several autophagy enhancer drugs identified from the recent drug screenings, including the phenothiazines, are thought to act on autophagy by mTOR-independent mechanism(s) [17, 23, 24]. One of the phenothiazines that have been investigated, fluspirilene, is thought to induce autophagy by reducing intracellular Ca2+ and preventing calpain-1-mediated cleavage of autophagy gene ATG5 [26]. The mood-stabilizing effects of lithium are thought to involve inhibition of IMPase and prevention of inositol recycling, while CBZ and valproic acid appear to act on Ins [24, 25]. The inhibition of IMPase or Ins leads to reduced intracellular inositol and IP3 levels, which therefore induce autophagy. However, the precise mechanism by which autophagy is regulated by the calcium-related signaling pathway or the phosphatidylinositol signaling pathway has not been elucidated. In addition, further work on whether these targets are truly independent of mTOR is needed.
