Novel Treatment Strategies for Liver Disease Due to α1-antitrypsin Deficiency

Overview

Journal Clin Transl Sci

Specialties Biomedical Engineering
General Medicine

Date 2012 Jun 13

PMID 22686209

Citations 4

Authors

Nicholas Maurice

David H Perlmutter

Affiliations

Soon will be listed here.

Abstract

Alpha1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children and is also a cause of chronic hepatic fibrosis, cirrhosis, and hepatocellular carcinoma in adults. Recent advances in understanding how mutant AT molecules accumulate within hepatocytes and cause liver cell injury have led to a novel strategy for chemoprophylaxis of this liver disease. This strategy involves a class of drugs, which enhance the intracellular degradation of mutant AT and, because several of these drugs have been used safely in humans for other indications, the strategy can be moved immediately into clinical trials. In this review, we will also report on advances that provide a basis for several other strategies that could be used in the future for treatment of the liver disease associated with AT deficiency.

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References

Perlmutter D . Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency. Pediatr Res. 2006; 60(2):233-8. DOI: 10.1203/01.pdr.0000228350.61496.90. View

Qu D, Teckman J, Omura S, Perlmutter D . Degradation of a mutant secretory protein, alpha1-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. J Biol Chem. 1996; 271(37):22791-5. DOI: 10.1074/jbc.271.37.22791. View

Perlmutter D . Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates. Annu Rev Med. 2010; 62:333-45. DOI: 10.1146/annurev-med-042409-151920. View

An J, Blomenkamp K, Lindblad D, Teckman J . Quantitative isolation of alphalAT mutant Z protein polymers from human and mouse livers and the effect of heat. Hepatology. 2004; 41(1):160-7. DOI: 10.1002/hep.20508. View

Janus E, PHILLIPS N, Carrell R . Smoking, lung function, and alpha 1-antitrypsin deficiency. Lancet. 1985; 1(8421):152-4. DOI: 10.1016/s0140-6736(85)91916-6. View

Zhang L, Yu J, Pan H, Hu P, Hao Y, Cai W . Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci U S A. 2007; 104(48):19023-8. PMC: 2141901. DOI: 10.1073/pnas.0709695104. View

Teckman J, Gilmore R, Perlmutter D . Role of ubiquitin in proteasomal degradation of mutant alpha(1)-antitrypsin Z in the endoplasmic reticulum. Am J Physiol Gastrointest Liver Physiol. 2000; 278(1):G39-48. DOI: 10.1152/ajpgi.2000.278.1.G39. View

Piitulainen E, Carlson J, Ohlsson K, Sveger T . Alpha1-antitrypsin deficiency in 26-year-old subjects: lung, liver, and protease/protease inhibitor studies. Chest. 2005; 128(4):2076-81. DOI: 10.1378/chest.128.4.2076. View

Zhou H, Ko Y, Fischer H . Is heterozygous alpha-1-antitrypsin deficiency type PIZ a risk factor for primary liver carcinoma?. Cancer. 2000; 88(12):2668-76. DOI: 10.1002/1097-0142(20000615)88:12<2668::aid-cncr4>3.0.co;2-g. View

10.

Hidvegi T, Ewing M, Hale P, Dippold C, Beckett C, Kemp C . An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science. 2010; 329(5988):229-32. DOI: 10.1126/science.1190354. View

11.

Carlson J, Rogers B, Sifers R, Hawkins H, Finegold M, Woo S . Multiple tissues express alpha 1-antitrypsin in transgenic mice and man. J Clin Invest. 1988; 82(1):26-36. PMC: 303472. DOI: 10.1172/JCI113580. View

12.

Hidvegi T, Schmidt B, Hale P, Perlmutter D . Accumulation of mutant alpha1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFkappaB, and BAP31 but not the unfolded protein response. J Biol Chem. 2005; 280(47):39002-15. DOI: 10.1074/jbc.M508652200. View

13.

Yamasaki M, Li W, Johnson D, Huntington J . Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization. Nature. 2008; 455(7217):1255-8. DOI: 10.1038/nature07394. View

14.

Chen C, Zheng B, Han J, Lin S . Characterization of a novel mammalian RGS protein that binds to Galpha proteins and inhibits pheromone signaling in yeast. J Biol Chem. 1997; 272(13):8679-85. DOI: 10.1074/jbc.272.13.8679. View

15.

Crystal R . Alpha 1-antitrypsin deficiency, emphysema, and liver disease. Genetic basis and strategies for therapy. J Clin Invest. 1990; 85(5):1343-52. PMC: 296579. DOI: 10.1172/JCI114578. View

16.

Ding J, Yannam G, Roy-Chowdhury N, Hidvegi T, Basma H, Rennard S . Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes. J Clin Invest. 2011; 121(5):1930-4. PMC: 3083768. DOI: 10.1172/JCI45260. View

17.

Kamimoto T, Shoji S, Hidvegi T, Mizushima N, Umebayashi K, Perlmutter D . Intracellular inclusions containing mutant alpha1-antitrypsin Z are propagated in the absence of autophagic activity. J Biol Chem. 2005; 281(7):4467-76. DOI: 10.1074/jbc.M509409200. View

18.

Teckman J, An J, Loethen S, Perlmutter D . Fasting in alpha1-antitrypsin deficient liver: constitutive [correction of consultative] activation of autophagy. Am J Physiol Gastrointest Liver Physiol. 2002; 283(5):G1156-65. DOI: 10.1152/ajpgi.00041.2002. View

19.

Cruz P, Mueller C, Cossette T, Golant A, Tang Q, Beattie S . In vivo post-transcriptional gene silencing of alpha-1 antitrypsin by adeno-associated virus vectors expressing siRNA. Lab Invest. 2007; 87(9):893-902. DOI: 10.1038/labinvest.3700629. View

20.

Klionsky D, Emr S . Autophagy as a regulated pathway of cellular degradation. Science. 2000; 290(5497):1717-21. PMC: 2732363. DOI: 10.1126/science.290.5497.1717. View