{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T08:50:16Z","timestamp":1778575816150,"version":"3.51.4"},"reference-count":77,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T00:00:00Z","timestamp":1674777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Alpha-1 Foundation (USA)","award":["675023"],"award-info":[{"award-number":["675023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Individuals homozygous for the Pi*Z allele of SERPINA1 (ZAAT) are susceptible to lung disease due to insufficient \u03b11-antitrypsin secretion into the circulation and may develop liver disease due to compromised protein folding that leads to inclusion body formation in the endoplasmic reticulum (ER) of hepatocytes. Transgenic zebrafish expressing human ZAAT show no signs of hepatic accumulation despite displaying serum insufficiency, suggesting the defect in ZAAT secretion occurs independently of its tendency to form inclusion bodies. In this study, proteomic, transcriptomic, and biochemical analysis provided evidence of suppressed Srebp2-mediated cholesterol biosynthesis in the liver of ZAAT-expressing zebrafish. To investigate the basis for this perturbation, CRISPR\/Cas9 gene editing was used to manipulate ER protein quality control factors. Mutation of erlec1 resulted in a further suppression in the cholesterol biosynthesis pathway, confirming a role for this ER lectin in targeting misfolded ZAAT for ER-associated degradation (ERAD). Mutation of the two ER mannosidase homologs enhanced ZAAT secretion without inducing hepatic accumulation. These insights into hepatic ZAAT processing suggest potential therapeutic targets to improve secretion and alleviate serum insufficiency in this form of the \u03b11-antitrypsin disease.<\/jats:p>","DOI":"10.3390\/ijms24032475","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T04:31:27Z","timestamp":1675053087000},"page":"2475","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Expression of the Z Variant of \u03b11-Antitrypsin Suppresses Hepatic Cholesterol Biosynthesis in Transgenic Zebrafish"],"prefix":"10.3390","volume":"24","author":[{"given":"Connie","family":"Fung","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne 3800, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0180-0224","authenticated-orcid":false,"given":"Brendan","family":"Wilding","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne 3800, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8738-1878","authenticated-orcid":false,"given":"Ralf B.","family":"Schittenhelm","sequence":"additional","affiliation":[{"name":"Monash Proteomics and Metabolomics Facility, Monash University, Melbourne 3800, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9501-8208","authenticated-orcid":false,"given":"Robert J.","family":"Bryson-Richardson","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Monash University, Melbourne 3800, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phillip I.","family":"Bird","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne 3800, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3931","DOI":"10.1016\/S0021-9258(19)85615-6","article-title":"Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin","volume":"255","author":"Beatty","year":"1980","journal-title":"J. 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