Capitalizing on the autophagic response for treatment of liver disease caused by alpha-1-antitrypsin deficiency and other genetic diseases

Abstract

Alpha-1-antitrypsin deficiency (ATD) is one of the most common genetic causes of liver disease and is a prototype of liver diseases caused by the pathologic accumulation of aggregated mutant alpha-1-antitrypsin Z (ATZ) within liver cells. In the case of ATD-associated liver disease, the resulting "gain-of-function" toxicity can lead to serious clinical manifestations, including cirrhosis and hepatocellular carcinoma. Currently, the only definitive therapy for ATD-associated liver disease is liver transplantation, but recent efforts have demonstrated the exciting potential for novel therapies that target disposal of the mutant protein aggregates by harnessing a cellular homeostasis mechanism called autophagy. In this review, we will summarize research advances on autophagy and genetic liver diseases. We will discuss autophagy enhancer strategies for liver disease due to ATD and another genetic liver disease, inherited hypofibrinogenemia, caused by the proteotoxic effects of a misfolded protein. On the basis of recent evidence that autophagy plays a role in cellular lipid degradation, we also speculate about autophagy enhancer strategies for treatment of hepatic lipid storage diseases such as cholesterol ester storage disease.

Figure 1

Accumulation of ATZ in liver specifically activates autophagy. Liver sections are stained with anti-GFP to enhance the fluorescent signal. (a) Sections from the GFP-LC3 mouse have GFP+ autophagosomes only in the starved state (right panel—starved for 24 h). (b) Sections from the Z × GFP-LC3 mouse have GFP+ autophagosomes; however, the mouse is fed, but only after doxycycline (Dox) is removed from the drinking water so that the ATZ gene is expressed (right panel). (c) Sections from the Saar × GFP-LC3 mouse (lower right) do not show autophagosomes when the AT Saar variant is expressed following withdrawal of Dox in the fed state, but starvation does lead to GFP+ autophagosomes (right panel). (d) GFP+ autophagosomes are present in the PiZ × GFP-LC3 mouse in the fed state, as this mouse has constitutive expression of ATZ. Reprint from reference [1] with permission.

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.