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Physiol."],"abstract":"<jats:p>Alcohol-associated liver disease (ALD) has been recognized as the most common cause of advanced liver disease worldwide, though mechanisms of pathogenesis remain incompletely understood. The X-linked inhibitor of apoptosis (XIAP) protein was originally described as an anti-apoptotic protein that directly binds and inhibits caspases-3, 7, and 9. Here, we investigated the function of XIAP in hepatocytes <jats:italic>in vitro<\/jats:italic> using gain and loss-of-function approaches. We noted an XIAP-dependent increase in caspase activation as well as increased inflammatory markers and pro-inflammatory EV release from hepatocytes <jats:italic>in vitro<\/jats:italic>. Primary hepatocytes (PMH) from <jats:italic>Xiap<\/jats:italic><jats:sup><jats:italic>Alb.Cre<\/jats:italic><\/jats:sup> and <jats:italic>Xiap<\/jats:italic><jats:sup><jats:italic>loxP<\/jats:italic><\/jats:sup> mice exhibited higher cell death but surprisingly, lower expression of inflammation markers. Conditioned media from these isolated <jats:italic>Xiap<\/jats:italic> deleted PMH further decrease inflammation in bone marrow-derived macrophages. Also, interestingly, when administered an ethanol plus Fas-agonist-Jo2 model and an ethanol plus CCl4 model, these animals failed to develop an exacerbated disease phenotype <jats:italic>in vivo<\/jats:italic>. Of note, neither <jats:italic>Xiap<\/jats:italic><jats:sup><jats:italic>Alb<\/jats:italic><\/jats:sup>.<jats:sup><jats:italic>Cre<\/jats:italic><\/jats:sup> nor <jats:italic>Xiap<\/jats:italic><jats:sup><jats:italic>AAV8.Cre<\/jats:italic><\/jats:sup> mice presented with aggravated liver injury, hepatocyte apoptosis, liver steatosis, or fibrosis. Since therapeutics targeting XIAP are currently in clinical trials and caspase-induced death is very important for development of ALD, we sought to explore the potential basis of this unexpected lack of effect. We utilized scRNA-seq and spatially reconstructed hepatocyte transcriptome data from human liver tissue and observed that <jats:italic>XIAP<\/jats:italic> was significantly zonated, along with its endogenous inhibitor second mitochondria-derived activator of caspases (SMAC) in periportal region. This contrasted with pericentral zonation of other IAPs including cIAP1 and Apollon as well as caspases 3, 7, and 9. Thus providing a potential explanation for compensation of the effect of <jats:italic>Xiap<\/jats:italic> deletion by other IAPs. In conclusion, our findings implicate a potential zonallydependent role for SMAC that prevented development of a phenotype in XIAP knockout mice in ALD models. Targeting SMAC may also be important in addition to current efforts of targeting XIAP in treatment of ALD.<\/jats:p>","DOI":"10.3389\/fphys.2021.664222","type":"journal-article","created":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T15:27:42Z","timestamp":1620401262000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["XIAP Knockdown in Alcohol-Associated Liver Disease Models Exhibits Divergent in vitro and in vivo Phenotypes Owing to a Potential Zonal Inhibitory Role of SMAC"],"prefix":"10.3389","volume":"12","author":[{"given":"Li","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tejasav S.","family":"Sehrawat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas 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