Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates
Alpha-1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children. The primary pathological issue is a point mutation that renders an abundant hepatic secretory glycoprotein prone to altered folding and a tendency to polymerize and aggregate. However, the expression o...
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| Veröffentlicht in: | Annual review of medicine 2011-01, Vol.62 (1), p.333-345 |
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| creator | Perlmutter, David H |
| description | Alpha-1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children. The primary pathological issue is a point mutation that renders an abundant hepatic secretory glycoprotein prone to altered folding and a tendency to polymerize and aggregate. However, the expression of serious liver damage among homozygotes is dependent on genetic and/or environmental modifiers. Several studies have validated the concept that endogenous hepatic pathways for disposal of aggregation-prone proteins, including the proteasomal and autophagic degradative pathways, could play a key role in the variation in hepatic damage and be the target of the modifiers. Exciting recent results have shown that a drug that enhances autophagy can reduce the hepatic load of aggregated protein and reverse fibrosis in a mouse model of this disease. |
| doi_str_mv | 10.1146/annurev-med-042409-151920 |
| format | Article |
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Exciting recent results have shown that a drug that enhances autophagy can reduce the hepatic load of aggregated protein and reverse fibrosis in a mouse model of this disease.</description><identifier>ISSN: 0066-4219</identifier><identifier>EISSN: 1545-326X</identifier><identifier>DOI: 10.1146/annurev-med-042409-151920</identifier><identifier>PMID: 20707674</identifier><language>eng</language><publisher>United States: Annual Reviews, Inc</publisher><subject>alpha 1-Antitrypsin - blood ; alpha 1-Antitrypsin - metabolism ; alpha 1-Antitrypsin Deficiency - complications ; alpha 1-Antitrypsin Deficiency - metabolism ; Animals ; Autophagy ; Carbamazepine - metabolism ; Carbamazepine - pharmacology ; Cell Transformation, Neoplastic - metabolism ; Genetics ; Hepatology ; Humans ; Liver - drug effects ; Liver - metabolism ; Liver - pathology ; Liver diseases ; Liver Diseases - etiology ; Liver Diseases - metabolism ; Liver Diseases - pathology ; Lung Diseases - drug therapy ; Lung Diseases - metabolism ; Mice ; Mutation ; Pediatrics ; Point Mutation ; Polymerization ; Proteasome Endopeptidase Complex - metabolism ; Protein Folding ; Proteins</subject><ispartof>Annual review of medicine, 2011-01, Vol.62 (1), p.333-345</ispartof><rights>Copyright Annual Reviews, Inc. 2011</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-c4832b3821bfb002b15343182d6c821f52143b93bcd299bd72d02ce11eb86b43</citedby><cites>FETCH-LOGICAL-a449t-c4832b3821bfb002b15343182d6c821f52143b93bcd299bd72d02ce11eb86b43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,4168,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20707674$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Perlmutter, David H</creatorcontrib><title>Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates</title><title>Annual review of medicine</title><addtitle>Annu Rev Med</addtitle><description>Alpha-1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children. The primary pathological issue is a point mutation that renders an abundant hepatic secretory glycoprotein prone to altered folding and a tendency to polymerize and aggregate. However, the expression of serious liver damage among homozygotes is dependent on genetic and/or environmental modifiers. Several studies have validated the concept that endogenous hepatic pathways for disposal of aggregation-prone proteins, including the proteasomal and autophagic degradative pathways, could play a key role in the variation in hepatic damage and be the target of the modifiers. Exciting recent results have shown that a drug that enhances autophagy can reduce the hepatic load of aggregated protein and reverse fibrosis in a mouse model of this disease.</description><subject>alpha 1-Antitrypsin - blood</subject><subject>alpha 1-Antitrypsin - metabolism</subject><subject>alpha 1-Antitrypsin Deficiency - complications</subject><subject>alpha 1-Antitrypsin Deficiency - metabolism</subject><subject>Animals</subject><subject>Autophagy</subject><subject>Carbamazepine - metabolism</subject><subject>Carbamazepine - pharmacology</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Genetics</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Liver diseases</subject><subject>Liver Diseases - etiology</subject><subject>Liver Diseases - metabolism</subject><subject>Liver Diseases - pathology</subject><subject>Lung Diseases - drug therapy</subject><subject>Lung Diseases - metabolism</subject><subject>Mice</subject><subject>Mutation</subject><subject>Pediatrics</subject><subject>Point Mutation</subject><subject>Polymerization</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Protein Folding</subject><subject>Proteins</subject><issn>0066-4219</issn><issn>1545-326X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkctu1TAURS0EopfCL6DAhJHBrzzMrKqAVqrEpANm1vEjqavEDrZTdP-Ez8VXuZ0wsnTO2ttHWgh9oOQzpaL7AiFsyT3hxVlMBBNEYtpSycgLdKCtaDFn3a-X6EBI12HBqLxAb3J-JIRIzofX6IKRnvRdLw7o79W8PgCmGELxJR3X7ENj3eiNd8EcvzZ-WWMqEIxr4tisKRYHOS4wNxBsA1uJNT95U0NTAgvFP7lmhfLwB465OZX5vMZc-Rqf6zKdJrXDYcg5Gg_F2b23wjBNyU11lN-iVyPM2b07v5fo_vu3--sbfPfzx-311R0GIWTBRgycaT4wqkdNCNO05YLTgdnO1OHYMiq4llwby6TUtmeWMOModXrotOCX6NNeWy_4vblc1OKzcfMMwcUtq0EQLvqBt5X8-B_5GLcU6m0VGnrGWyYrJHfIpJhzcqNak18gHRUl6uROnd2p6k7t7tTurmbfnz_Y9Gn7nHyWxf8B0aOcDQ</recordid><startdate>20110101</startdate><enddate>20110101</enddate><creator>Perlmutter, David H</creator><general>Annual Reviews, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7T5</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20110101</creationdate><title>Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates</title><author>Perlmutter, David H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a449t-c4832b3821bfb002b15343182d6c821f52143b93bcd299bd72d02ce11eb86b43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>alpha 1-Antitrypsin - 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| ispartof | Annual review of medicine, 2011-01, Vol.62 (1), p.333-345 |
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| source | Annual Reviews; MEDLINE |
| subjects | alpha 1-Antitrypsin - blood alpha 1-Antitrypsin - metabolism alpha 1-Antitrypsin Deficiency - complications alpha 1-Antitrypsin Deficiency - metabolism Animals Autophagy Carbamazepine - metabolism Carbamazepine - pharmacology Cell Transformation, Neoplastic - metabolism Genetics Hepatology Humans Liver - drug effects Liver - metabolism Liver - pathology Liver diseases Liver Diseases - etiology Liver Diseases - metabolism Liver Diseases - pathology Lung Diseases - drug therapy Lung Diseases - metabolism Mice Mutation Pediatrics Point Mutation Polymerization Proteasome Endopeptidase Complex - metabolism Protein Folding Proteins |
| title | Alpha-1-antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease-associated protein aggregates |
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