{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:07:18Z","timestamp":1790946438360,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","license":[{"start":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T00:00:00Z","timestamp":1653609600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Alpha\u20101 antitrypsin (AAT) deficiency (AATD) is an inherited disease caused by mutations in the serpin family A member 1 (\n                    <jats:italic toggle=\"yes\">SERPINA1<\/jats:italic>\n                    , also known as\n                    <jats:italic toggle=\"yes\">AAT<\/jats:italic>\n                    ) gene. The most common variant, PI*Z (Glu342Lys), causes accumulation of aberrantly folded AAT in the endoplasmic reticulum (ER) of hepatocytes that is associated with a toxic gain of function, hepatocellular injury, liver fibrosis, and hepatocellular carcinoma. The unfolded protein response (UPR) is a cellular response to improperly folded proteins meant to alleviate ER stress. It has been unclear whether PI*Z AAT elicits liver cell UPR, due in part to limitations of current cellular and animal models. This study investigates whether UPR is activated in a novel human PI*Z AAT cell line and a new PI*Z human AAT (hAAT) mouse model. A PI*Z AAT hepatocyte cell line (Huh7.5Z) was established using clustered regularly interspaced short palindromic repeats (CRISPR)\/Cas9 gene editing of the normal\n                    <jats:italic toggle=\"yes\">ATT<\/jats:italic>\n                    (PI*MM) gene in the Huh7.5 cell line. Additionally, novel full\u2010length genomic DNA PI*Z hAAT and PI*M hAAT transgenic mouse models were established. Using these new models, UPR in Huh7.5Z cells and PI*Z mice were comprehensively determined. Robust activation of UPR was observed in Huh7.5Z cells compared to Huh7.5 cells. Activated caspase cascade and apoptosis markers, increased chaperones, and autophagy markers were also detected in Z hepatocytes. Selective attenuation of UPR signaling branches was observed in PI*Z hAAT mice in which the protein kinase R\u2010like ER kinase and inositol\u2010requiring enzyme1\u03b1 branches were suppressed while the activating transcription factor 6\u03b1 branch remained active. This study provides direct evidence that PI*Z AAT triggers canonical UPR and that hepatocytes survive pro\u2010apoptotic UPR by selective suppression of UPR branches. Our data improve understanding of underlying pathological molecular mechanisms of PI*Z AATD liver disease.\n                  <\/jats:p>","DOI":"10.1002\/hep4.1997","type":"journal-article","created":{"date-parts":[[2022,5,27]],"date-time":"2022-05-27T05:41:12Z","timestamp":1653630072000},"page":"2354-2367","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":28,"title":["The unfolded protein response to PI*Z alpha\u20101 antitrypsin in human hepatocellular and murine models"],"prefix":"10.1097","volume":"6","author":[{"given":"Yuanqing","family":"Lu","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine,Department of Medicine,University of Florida,Florida,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqun R.","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine,Department of Medicine,University of Florida,Florida,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungnam","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine,Department of Medicine,University of Florida,Florida,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naweed S.","family":"Mohammad","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine,Department of Medicine,University of Florida,Florida,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alek M.","family":"Aranyos","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine,Department of Medicine,University of Florida,Florida,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calvin","family":"Gould","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine,Department of Medicine,University of Florida,Florida,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4659-1622","authenticated-orcid":false,"given":"Nazli","family":"Khodayari","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine,Department of Medicine,University of Florida,Florida,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina A.","family":"Oshins","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine,Department of Medicine,University of Florida,Florida,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig G.","family":"Moneypenny","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine,Department of Medicine,University of Florida,Florida,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0189-1565","authenticated-orcid":false,"given":"Mark L.","family":"Brantly","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care and Sleep Medicine,Department of Medicine,University of Florida,Florida,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,5,27]]},"reference":[{"key":"hep41997-bib-0001-20241118","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1038\/35038119","article-title":"Structure of a serpin\u2010protease complex shows inhibition by deformation","volume":"407","year":"2000","journal-title":"Nature"},{"key":"hep41997-bib-0002-20241118","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1084\/jem.166.4.1041","article-title":"Lipopolysaccharide modulates the expression of alpha 1 proteinase inhibitor and other serine proteinase inhibitors in 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