Loss of CEACAM1 in endothelial cells causes hepatic fibrosis

Muturi, Harrison T.; Ghadieh, Hilda E.; Abdolahipour, Raziyeh; Stankus, Hannah L.; Belew, Getachew Debas; Liu, James K.; Jahromi, Marziyeh Salehi; Lee, Abraham D.; Singer, Bernhard B.; Angeli-Pahim, Isabella; Sehrawat, Tejasav S.; Malhi, Harmeet; Verhulst, Stefaan; Grunsven, Leo A. van; Zarrinpar, Ali; Duarte, Sergio; Najjar, Sonia M.

doi:10.1016/j.metabol.2023.155562

Cited by 4 publications

(18 citation statements)

References 48 publications

(97 reference statements)

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“…We have previously shown that hepatic CEACAM1 expression is progressively reduced with advancing fibrosis stages in patients with MASH [15]. Moreover, single cell RNA-sequencing showed lower CEACAM1 expression in hepatocytes and LSECs of patients with fibrosis/cirrhosis [17]. S.M.N.…”

Section: Discussionmentioning

confidence: 94%

“…Microscope and 10 randomly selected high power fields (20X) per sample were imaged with ImageJ (v1.53t) to quantify Sirius Red stain as %area [17].…”

Section: Liver Histology and Immunohistochemical Analysismentioning

confidence: 99%

“…For immunohistochemical (IHC) analysis, liver sections underwent antigen-retrieval, blocking with rabbit or mouse serum, stained overnight at 4°C with specific antibodies, blotted with species-specific biotinylated secondary antibodies before being hematoxylin-counterstained [17]. Images were taken using Nikon Eclipse 90i Microscope and evaluated blindly to count positively stained cells in 5 fields/mouse at 40X magnification.…”

Section: Liver Histology and Immunohistochemical Analysismentioning

confidence: 99%

“…As previously described [17], cells were Triton-lysed and subjected to SDS-PAGE followed by Western blot analysis using antibodies as listed in Supplemental data. Proteins were detected by chemiluminescence, scanned and their density normalized against tubulin (Cell Signaling) or the total amount of proteins of the signaling molecule applied on parallel gels.…”

Section: Immunoprecipitation and Western Blot Analysismentioning

confidence: 99%

“…Reciprocally, liver-specific rescuing of CEACAM1 reverses metabolic dysregulation and hepatic fibrosis in global Cc1 −/− null mice [14]. In contrast, CEACAM1 loss in endothelial cells promotes hepatic fibrosis, driven by increased production of endothelin1, without insulin resistance or hepatic steatosis [17]. Consistent with these data in genetically-modified mice, patients with MASH exhibit a progressive loss of CEACAM1 in liver [15] and particularly in LSECs [17] as the disease advances.…”

Section: Introductionmentioning

confidence: 99%

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Conditional deletion of CEACAM1 causes hepatic stellate cell activation

Muturi,

Ghadieh,

Asalla

et al. 2024

Preprint

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ObjectivesHepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with MASH. Global and hepatocyte-specific deletions ofCeacam1impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPARγ on CEACAM1 transcriptoin and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation.MethodsWe examined whether lentiviral shRNA-mediated CEACAM1 donwregulation (KD-LX2) activates cultured human LX2 stellate cells. We also generatedLratCre+Cc1fl/flmutants with conditionalCeacam1deletion in HSCs and characterized their MASH phenotype. Media transfer experiments were employed to examine whether media from mutant human and murine HSCs activate their wild-type counterparts.ResultsLratCre+Cc1fl/flmutants displayed hepatic inflammation and fibrosis but without insulin resistance or hepatic steatosis. Their HSCs, like KD-LX2 cells, underwent myofibroblastic transformation and their media activated wild-type HDCs. This was inhibited by nicotinic acid treatment which stemmed the release of IL-6 and fatty acids, both of which activate the epidermal growth factor receptor (EGFR) tyrosine kinase. Gefitinib inhibition of EGFR and its downstream NF-κB/IL-6/STAT3 inflammatory and MAPK-proliferation pathways also blunted HSCs activation in the absence of CEACAM1.ConclusionsLoss of CEACAM1 in HSCs provoked their myofibroblastic transformation in the absence of insulin resistance and hepatic steatosis. This response is mediated by autocrine HSCs activation of the EGFR pathway that amplifies inflammation and proliferation.

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Section: Discussionmentioning

confidence: 94%

“…Microscope and 10 randomly selected high power fields (20X) per sample were imaged with ImageJ (v1.53t) to quantify Sirius Red stain as %area [17].…”

Section: Liver Histology and Immunohistochemical Analysismentioning

confidence: 99%

Section: Liver Histology and Immunohistochemical Analysismentioning

confidence: 99%

Section: Immunoprecipitation and Western Blot Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Conditional deletion of CEACAM1 causes hepatic stellate cell activation

Muturi,

Ghadieh,

Asalla

et al. 2024

Preprint

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Bioinformatics and next generation data analysis reveals the potential role of inflammation in sepsis and its associated complications

Vastrad¹,

Vastrad²

2023

Preprint

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Sepsis is the leading systemic inflammatory response syndrome in worldwide, yet relatively little is known about the genes and signaling pathways involved in sepsis progression. The current investigation aimed to elucidate potential key candidate genes and pathways in sepsis and its associated complications. Next generation sequencing (NGS) dataset (GSE185263) was downloaded from the Gene Expression Omnibus (GEO) database, which included data from 348 sepsis samples and 44 normal control samples. Differentially expressed genes (DEGs) were identified using t-tests in the DESeq2 R package. Next, we made use of the g:Profiler to analyze gene ontology (GO) and REACTOME pathway. Then protein-protein interaction (PPI) of these DEGs was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING). Furthermore, we constructed miRNA-hub gene regulatory network and TF-hub gene regulatory network among hub genes utilizing miRNet and NetworkAnalyst online databases tool and Cytoscape software. Finally, we performed receiver operating characteristic (ROC) curve analysis of hub genes through the pROC package in R statistical software. In total, 958 DEGs were identified, of which 479 were up regulated and 479 were down regulated. GO and REACTOME results showed that DEGs mainly enriched in regulation of cellular process, response to stimulus, extracellular matrix organization and immune system. The hub genes of PRKN, KIT, FGFR2, GATA3, ERBB3, CDK1, PPARG, H2BC5, H4C4 and CDC20 might be associated with sepsis and its associated complications. Predicted miRNAs (e.g., hsa-mir-548ad-5p and hsa-mir-2113) and TFs (e.g., YAP1 and TBX5) were found to be significantly correlated with sepsis and its associated complications. In conclusion, the DEGs, relative pathways, hub genes, miRNA and TFs identified in the current investigation might help in understanding of the molecular mechanisms underlying sepsis and its associated complications progression and provide potential molecular targets and biomarkers for sepsis and its associated complications.

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Loss of CEACAM1 in hepatocytes causes hepatic fibrosis

Zaidi,

Asalla,

Muturi

et al. 2024

Eur J Clin Investigation

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BackgroundThe role of insulin resistance in hepatic fibrosis in Metabolic dysfunction‐Associated SteatoHepatitis (MASH) remains unclear. Carcinoembryonic Antigen‐related Cell Adhesion Molecule1 protein (CEACAM1) promotes insulin clearance to maintain insulin sensitivity and repress de novo lipogenesis, as bolstered by the development of insulin resistance and steatohepatitis in AlbuminCre + Cc1fl/fl mice with liver‐specific mouse gene encoding CEACAM1 protein (Ceacam1) deletion. We herein investigated whether these mice also developed hepatic fibrosis and whether hepatic CEACAM1 is reduced in patients with MASH at different fibrosis stages.MethodsAlbuminCre + Cc1fl/fl mice were fed a regular or a high‐fat diet before their insulin metabolism and action were assessed during IPGTT, and their livers excised for histochemical, immunohistochemical and Western blot analysis. Sirius red staining was used to assess fibrosis, and media transfer was employed to examine whether mutant hepatocytes activated hepatic stellate cells (HSCs). Hepatic CEACAM1 protein levels in patients with varying disease stages were assessed by ELISA.ResultsHepatocytic deletion of Ceacam1 caused hyperinsulinemia‐driven insulin resistance emanating from reduced hepatic insulin clearance. AlbuminCre + Cc1fl/fl livers showed inflammation, fibrosis and hepatic injury, with more advanced bridging and chicken‐wire hepatic fibrosis under high‐fat conditions. Media transferred from hepatocytes isolated from mutant mice activated control HSCs, likely owing to their elevated endothelin1 content. Interestingly, hepatic CEACAM1 levels were lower in the livers of patients with MASH and declined gradually with advanced fibrosis stage.ConclusionsHepatic CEACAM1 levels declined with progression of MASH in humans. The phenotype of AlbuminCre + Cc1fl/fl mice assigned a key role to CEACAM1 loss from hepatocytes in hepatic fibrosis independently of other liver cells.

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Loss of CEACAM1 in endothelial cells causes hepatic fibrosis

Cited by 4 publications

References 48 publications

Conditional deletion of CEACAM1 causes hepatic stellate cell activation

Conditional deletion of CEACAM1 causes hepatic stellate cell activation

Bioinformatics and next generation data analysis reveals the potential role of inflammation in sepsis and its associated complications

Loss of CEACAM1 in hepatocytes causes hepatic fibrosis

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