XIAP Knockdown in Alcohol-Associated Liver Disease Models Exhibits Divergent <i>in vitro</i> and <i>in vivo</i> Phenotypes Owing to a Potential Zonal Inhibitory Role of SMAC

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dc.contributor.authorHe, Li
dc.contributor.authorSehrawat, Tejasav S.
dc.contributor.authorVerma, Vikas K.
dc.contributor.authorNavarro-Corcuera, Amaia
dc.contributor.authorSidhu, Guneet
dc.contributor.authorMauer, Amy
dc.contributor.authorLuo, Xin
dc.contributor.authorKatsumi, Tomohiro
dc.contributor.authorChen, Jingbiao
dc.contributor.authorShah, Soni
dc.contributor.authorArab, Juan Pablo
dc.contributor.authorCao, Sheng
dc.contributor.authorKashkar, Hamid
dc.contributor.authorGores, Gregory J.
dc.contributor.authorMalhi, Harmeet
dc.contributor.authorShah, Vijay H.
dc.date.accessioned2025-01-20T22:22:48Z
dc.date.available2025-01-20T22:22:48Z
dc.date.issued2021
dc.description.abstractAlcohol-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 in vitro 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 in vitro. Primary hepatocytes (PMH) from Xiap(Alb.Cre) and Xiap(loxP) mice exhibited higher cell death but surprisingly, lower expression of inflammation markers. Conditioned media from these isolated Xiap 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 in vivo. Of note, neither Xiap(Alb).(Cre) nor Xiap(AAV8.Cre) 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 XIAP 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 Xiap 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.
dc.fuente.origenWOS
dc.identifier.doi10.3389/fphys.2021.664222
dc.identifier.eissn1664-042X
dc.identifier.urihttps://doi.org/10.3389/fphys.2021.664222
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/94687
dc.identifier.wosidWOS:000652513500001
dc.language.isoen
dc.revistaFrontiers in physiology
dc.rightsacceso restringido
dc.subjectALD
dc.subjectapoptosis
dc.subjectscRNA sequencing
dc.subjectIAP
dc.subjectalcoholic hepatitis
dc.subjectalcohol-associated liver disease
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleXIAP Knockdown in Alcohol-Associated Liver Disease Models Exhibits Divergent <i>in vitro</i> and <i>in vivo</i> Phenotypes Owing to a Potential Zonal Inhibitory Role of SMAC
dc.typeartículo
dc.volumen12
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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