Capitalizing on the Autophagic Response for Treatment of Liver Disease Caused by Alpha-1-Antitrypsin Deficiency and Other Genetic Diseases

Chu, Andrew S.; Perlmutter, David H.; Wang, Yan

doi:10.1155/2014/459823

Cited by 15 publications

(15 citation statements)

References 46 publications

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“…33 Isolated PiZ mouse hepatocytes are susceptible to decreased proliferation and increased apoptosis with increasing ATZ globule load. 34,35 Taken together, these studies confirm that GD hepatocytes exhibit increased survival and regenerative capacity in times of stress. As a preclinical model, the PiZ mouse offers a unique opportunity to study mechanisms of protein clearance of ATZ globules.…”

Section: Piz Mouse Model Of A1atdsupporting

confidence: 61%

Pathogenesis of Alpha-1 Antitrypsin Deficiency in the Liver: New Approaches to Old Questions

Khan¹

2016

JLRDT

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Alpha-1 Antitrypsin deficiency (A1ATD) can progress to cirrhosis and hepatocellular carcinoma; however, not all patients are susceptible to severe liver disease. Liver transplantation is the only cure for A1ATD-related liver disease. A1ATD is caused by a toxic gain-of-function mutation in the human SERPINA1 gene, generating mis folded ATZ protein "globules" in hepatocytes. These insoluble aggregates overwhelm protein clearance pathways and lead to chronic intracellular stress. This review serves to summarize the basic hepatic mechanisms involved in A1ATD, as described in relevant in vitro and animal models. Potential treatments such as autophagy-enhancing agents and molecular therapies are also discussed. Clinical trials are underway to further assess some of these novel approaches in patients, but more safety and efficacy data is needed to successfully translate these interventions from the laboratory to the clinic.

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Section: Piz Mouse Model Of A1atdsupporting

confidence: 61%

Pathogenesis of Alpha-1 Antitrypsin Deficiency in the Liver: New Approaches to Old Questions

Khan¹

2016

JLRDT

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“…While liver transplantation is the only curative treatment available at this time, there have been several developments towards alternative therapies that would preserve the native liver. Autophagy has been a major target for therapeutic strategies because of the key role that it plays in the intracellular degradation of ATZ [ 12 ]. Both physical modifications and drug targets are being utilized to explore mechanisms to increase autophagy.…”

Section: Introductionmentioning

confidence: 99%

Liver Disease in Alpha-1 Antitrypsin Deficiency: Current Approaches and Future Directions

Mitchell

Khan

2017

Curr Pathobiol Rep

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Purpose of ReviewThe aim of the study is to review the liver disease caused by alpha-1 antitrypsin deficiency (A1ATD), including pathogenesis, epidemiology, diagnostic testing, and recent therapeutic developments.Recent FindingsTherapeutic approaches target several intracellular pathways to reduce the cytotoxic effects of the misfolded mutant globular protein (ATZ) on the hepatocyte. These include promoting ATZ transport out of the endoplasmic reticulum (ER), enhancing ATZ degradation, and preventing ATZ globule-aggregation.SummaryA1ATD is the leading genetic cause of liver disease among children. It is a protein-folding disorder in which toxic insoluble ATZ proteins aggregate in the ER of hepatocytes leading to inflammation, fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma. The absence of the normal A1AT serum protein also predisposes patients to pan lobar emphysema as adults. At this time, the only approved therapy for A1ATD-associated liver disease is orthotopic liver transplantation, which is curative. However, there has been significant recent progress in the development of small molecule therapies with potential both to preserve the native liver and prevent hepatotoxicity.

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“…Within the lung, the loss-of-function of SERPINA1/AAT leading to dysregulated elastase activity is the main driver of emphysema and chronic obstructive pulmonary disease (COPD) 7, 8 . Although liver transplantation remains the only definitive therapy for SERPINA1/AAT-D-associated liver disease until now, recent studies have been searching for the potential targets for disposal of the toxic protein aggregates by harnessing a cellular metabolic homeostasis mechanism 9, 10 . Therefore, elucidating the mechanisms by which hepatocytes degrade SERPINA1 E342K /ATZ may lead to identification of novel therapeutic options for liver disease due to SERPINA1/AAT-D.…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin ligase SYVN1/HRD1 facilitates degradation of the SERPINA1 Z variant/α-1-antitrypsin Z variant via SQSTM1/p62-dependent selective autophagy

et al. 2017

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SERPINA1/AAT/α-1-antitrypsin (serpin family A member 1) deficiency (SERPINA1/ AAT-D) is an autosomal recessive disorder characterized by the retention of misfolded SERPINA1/AAT in the endoplasmic reticulum (ER) of hepatocytes and a significant reduction of serum SERPINA1/AAT level. The Z variant of SERPINA1/AAT, containing a Glu342Lys (E342K) mutation (SERPINA1E342K/ATZ), the most common form of SERPINA1/AAT-D, is prone to misfolding and polymerization, which retains it in the ER of hepatocytes and leads to liver injury. Both proteasome and macroautophagy/autophagy pathways are responsible for disposal of SERPINA1E342K/ATZ after it accumulates in the ER. However, the mechanisms by which SERPINA1E342K/ATZ is selectively degraded by autophagy remain unknown. Here, we showed that ER membrane-spanning ubiquitin ligase (E3) SYVN1/HRD1 enhances the degradation of SERPINA1E342K/ATZ through the autophagy-lysosome pathway. We found that SYVN1 promoted SERPINA1E342K/ATZ, especially Triton X 100-insoluble SERPINA1E342K/ATZ clearance. However, the effect of SYVN1 in SERPINA1E342K/ATZ clearance was impaired after autophagy inhibition, as well as in autophagy-related 5 (atg5) knockout cells. On the contrary, autophagy induction enhanced SYVN1-mediated SERPINA1E342K/ATZ degradation. Further study showed that SYVN1 mediated SERPINA1E342K/ATZ ubiquitination, which is required for autophagic degradation of SERPINA1E342K/ATZ by promoting the interaction between SERPINA1E342K/ATZ and SQSTM1/p62 for formation of the autophagy complex. Interestingly, SYVN1-mediated lysine 48 (K48)-linked polyubiquitin chains that conjugated onto SERPINA1E342K/ATZ might predominantly bind to the ubiquitin-associated (UBA) domain of SQSTM1 and couple the ubiquitinated SERPINA1E342K/ATZ to the lysosome for degradation. In addition, autophagy inhibition attenuated the suppressive effect of SYVN1 on SERPINA1E342K/ATZ cytotoxicity, and the autophagy inducer rapamycin enhanced the suppressive effect of SYVN1 on SERPINA1E342K/ATZ-induced cell apoptosis. Therefore, this study proved that SYVN1 enhances SERPINA1E342K/ATZ degradation through SQSTM1-dependent autophagy and attenuates SERPINA1E342K/ATZ cytotoxicity.

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Capitalizing on the Autophagic Response for Treatment of Liver Disease Caused by Alpha-1-Antitrypsin Deficiency and Other Genetic Diseases

Cited by 15 publications

References 46 publications

Pathogenesis of Alpha-1 Antitrypsin Deficiency in the Liver: New Approaches to Old Questions

Pathogenesis of Alpha-1 Antitrypsin Deficiency in the Liver: New Approaches to Old Questions

Liver Disease in Alpha-1 Antitrypsin Deficiency: Current Approaches and Future Directions

Ubiquitin ligase SYVN1/HRD1 facilitates degradation of the SERPINA1 Z variant/α-1-antitrypsin Z variant via SQSTM1/p62-dependent selective autophagy

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