Regulation of hepatic fibrosis by carcinoembryonic antigen-related cell adhesion molecule 1

Helal, Raghd Abu; Russo, Lucía; Ghadieh, Hilda E.; Muturi, Harrison T.; Asalla, Suman; Lee, Abraham D.; Gatto‐Weis, Cara; Najjar, Sonia M.

doi:10.1016/j.metabol.2021.154801

Cited by 11 publications

(20 citation statements)

References 51 publications

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“…significantly lower in KO versus WT mice for the ND but not the HFD (Figure 1B). Serum TG for WT mice were in accordance with the literature (17), but they differed from previously reported plasma levels (18). The weight changes in extrahepatic tissues (Figure 1C) were most dramatic in the visceral fat pad.…”

Section: How Might These Results Change the Direction Of Research?supporting

confidence: 86%

Reversal of obesity development in Ceacam1^−/− male mice by bone marrow transplantation or introduction of the human CEACAM1 gene

Zhang

Placa

Gugiu

et al. 2022

Obesity

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ObjectiveAlthough Ceacam1−/− male mice become obese on normal chow, the effect of bone marrow transplantation or introduction of the carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) gene has not been studied, to the knowledge of the authors.MethodsThis study analyzed Ceacam1−/− mice on normal diet or high‐fat diet (HFD), including effects of bone marrow transplantation or introduction of the CEACAM1 gene.ResultsMale Ceacam1−/− mice on normal diet versus HFD for 24 weeks gained significantly more weight than controls, and Ceacam1−/− mice aged up to 2 years had a high frequency of liver cancer. Transplantation of wild‐type bone marrow into Ceacam1−/− mice or introduction of the human CEACAM1 gene fully or partially reversed the obesity phenotype. Liver lipidomics on Ceacam1−/− versus wild‐type controls on an HFD revealed a significant increase in diacyl glycerides. An increase in fatty acid transporter CD36 levels further suggests that loss of Ceacam1 leads to a major dysregulation of free fatty acid uptake.ConclusionsCEACAM1 expression in both the liver and immune cells regulates obesity and lipid storage pathways in the liver. Bone marrow reconstitution of the immune system or introduction of the human CEACAM1 gene can fully or partially reverse the phenotype.

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Section: How Might These Results Change the Direction Of Research?supporting

confidence: 86%

Reversal of obesity development in Ceacam1^−/− male mice by bone marrow transplantation or introduction of the human CEACAM1 gene

Zhang

Placa

Gugiu

et al. 2022

Obesity

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“…NA treatment normalized these parameters in HSCs from Cc1 −/− and Cc1 +/+ /Cond cells (Table S3). This proposed that CEACAM1 loss in HSCs activated them and caused their myofibroblastic transformation to contribute to hepatic fibrosis in Cc1 −/− nulls [14].…”

Section: Resultsmentioning

confidence: 99%

“…As routinely done [9], male mice were kept in cages with Alpha-dri bedding (Shepherd Specialty Papers) and fasted for 6 hrs before being injected intraperitoneally with either 1.5g/kg BW dextrose solution (GTT or 0.75units/kg BW human regular insulin (Novo Nordisk, Princeton, NJ) (ITT) and their tail blood glucose was measured at 0-120 min (GTT) or 0-180 post-injection (ITT).…”

Section: Supplemental Materialsmentioning

confidence: 99%

“…Fed a high-fat diet, mice lacking CEACAM1 in hepatocytes develop advanced hepatocellular injury accompanied by chicken-wire fibrosis and apoptosis [14; 16]. 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].…”

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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“…Reversal of the metabolic phenotype upon liver-specific reconstitution of CEACAM1 further demonstrates the primary role of hepatic insulin clearance in the pathogenesis of insulin resistance [ 107 ]. Interestingly, high-fat feeding causes a progressive NASH phenotype in global Ceacam1 null mice, including a higher degree of macro-steatosis in parenchyma, and more robust hepatic fibrosis and apoptosis [ 108 ]. This advanced phenotype is prevented by rescuing CEACAM1 in the liver [ 108 ], providing further in vivo demonstration of the critical role that CEACAM1-dependent insulin clearance pathways play in the pathogenesis of hepatic insulin resistance and NAFLD/NASH.…”

Section: Reduction In Hepatic Insulin Clearance Plays a Primary Role ...mentioning

confidence: 99%

Regulation of Insulin Clearance by Non-Esterified Fatty Acids

et al. 2022

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Insulin stores lipid in adipocytes and prevents lipolysis and the release of non-esterified fatty acids (NEFA). Excessive release of NEFA during sustained energy supply and increase in abdominal adiposity trigger systemic insulin resistance, including in the liver, a major site of insulin clearance. This causes a reduction in insulin clearance as a compensatory mechanism to insulin resistance in obesity. On the other hand, reduced insulin clearance in the liver can cause chronic hyperinsulinemia, followed by downregulation of insulin receptor and insulin resistance. Delineating the cause–effect relationship between reduced insulin clearance and insulin resistance has been complicated by the fact that insulin action and clearance are mechanistically linked to insulin binding to its receptors. This review discusses how NEFA mobilization contributes to the reciprocal relationship between insulin resistance and reduced hepatic insulin clearance, and how this may be implicated in the pathogenesis of non-alcoholic fatty liver disease.

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Regulation of hepatic fibrosis by carcinoembryonic antigen-related cell adhesion molecule 1

Cited by 11 publications

References 51 publications

Reversal of obesity development in Ceacam1^−/− male mice by bone marrow transplantation or introduction of the human CEACAM1 gene

Reversal of obesity development in Ceacam1^−/− male mice by bone marrow transplantation or introduction of the human CEACAM1 gene

Conditional deletion of CEACAM1 causes hepatic stellate cell activation

Regulation of Insulin Clearance by Non-Esterified Fatty Acids

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Regulation of hepatic fibrosis by carcinoembryonic antigen-related cell adhesion molecule 1

Cited by 11 publications

References 51 publications

Reversal of obesity development in Ceacam1−/− male mice by bone marrow transplantation or introduction of the human CEACAM1 gene

Reversal of obesity development in Ceacam1−/− male mice by bone marrow transplantation or introduction of the human CEACAM1 gene

Conditional deletion of CEACAM1 causes hepatic stellate cell activation

Regulation of Insulin Clearance by Non-Esterified Fatty Acids

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Reversal of obesity development in Ceacam1^−/− male mice by bone marrow transplantation or introduction of the human CEACAM1 gene

Reversal of obesity development in Ceacam1^−/− male mice by bone marrow transplantation or introduction of the human CEACAM1 gene