Person: Gómez Del Moral Martín-Consuegra, Manuel María
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First Name
Manuel María
Last Name
Gómez Del Moral Martín-Consuegra
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Biología Celular
Area
Biología Celular
Identifiers
8 results
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Item An Experimental DUAL Model of Advanced Liver Damage(Hepatology Communications, 2021) Benede Ubieto, Raquel; Estévez Vázquez, Olga; Guo, Feifei; Chen, Chaobo; Gómez Del Moral Martín-Consuegra, Manuel María; Lamas Paz, Aranzazu; Morán, Laura; López Alcántara, Nuria; S. Mazariegos, Marina; Zheng, Kang; Juárez Martín-Delgado, Ignacio; Martín Villa, José Manuel; Asensio, Iris; Vaquero Martín, Francisco Javier; Peligros Gómez, María Isabel; Romero Gómez, Manuel; Bañares Cañizares, Rafael; Cubero Palero, Francisco Javier; Nevzorova, YuliaIndividuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.Item Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress(Frontiers in Immunology, 2023) Wculek, Stefanie K.; Fernández-Bravo, Sergio; Torres-Ruiz, Raúl; Gomez-Sánchez, Maria José; Hernández-Walias, José Carlos; Moraes Ferreira, Frederico; Corraliza, Ana María; Sancho, David; Esteban, Vanesa; Rodriguez-Perales, Sandra; Nakaya, Helder I.; Salas, Azucena; Campos-Martín, Yolanda; Martínez-Zamorano, Elena; Muñoz-López, Diego; Blumberg, Richard S.; Martín Adrados, Beatriz; Valle Noguera, Ana; Cruz Adalia, Aranzazu; Olivares Olivares, Bernardo David; Gómez Del Moral Martín-Consuegra, Manuel María; Cubero Palero, Francisco Javier; Martínez Naves, EduardoIntroduction: The Unfolded Protein Response, a mechanism triggered by the cell in response to Endoplasmic reticulum stress, is linked to inflammatory responses. Our aim was to identify novel Unfolded Protein Response-mechanisms that might be involved in triggering or perpetuating the inflammatory response carried out by the Intestinal Epithelial Cells in the context of Inflammatory Bowel Disease. Methods: We analyzed the transcriptional profile of human Intestinal Epithelial Cell lines treated with an Endoplasmic Reticulum stress inducer (thapsigargin) and/or proinflammatory stimuli. Several genes were further analyzed in colonic biopsies from Ulcerative Colitis patients and healthy controls. Lastly, we generated Caco-2 cells lacking HMGCS2 by CRISPR Cas-9 and analyzed the functional implications of its absence in Intestinal Epithelial Cells. Results: Exposure to a TLR ligand after thapsigargin treatment resulted in a powerful synergistic modulation of gene expression, which led us to identify new genes and pathways that could be involved in inflammatory responses linked to the Unfolded Protein Response. Key differentially expressed genes in the array also exhibited transcriptional alterations in colonic biopsies from active Ulcerative Colitis patients, including NKG2D ligands and the enzyme HMGCS2. Moreover, functional studies showed altered metabolic responses and epithelial barrier integrity in HMGCS2 deficient cell lines. Conclusion: We have identified new genes and pathways that are regulated by the Unfolded Protein Response in the context of Inflammatory Bowel Disease including HMGCS2, a gene involved in the metabolism of Short Chain Fatty Acids that may have an important role in intestinal inflammation linked to Endoplasmic Reticulum stress and the resolution of the epithelial damage.Item Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis(Cell death diseases, 2023) Kang, Zheng; Fengjie, Hao; Medrano García, Sandra; Chaobo, Chen; Morán Blanco, Laura; Peligros Gómez, María Isabel; Vaquero Martín, Francisco Javier; Bañares Cañizares, Rafael; Gómez Del Moral Martín-Consuegra, Manuel María; Regueiro González-Barros, José Ramón; Martínez Naves, Eduardo; Nevzorova, Yulia; Fernández Malavé, Edgar Gonzalo; Cubero Palero, Francisco JavierProgressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS−/−) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS−/− mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS−/− livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.Item Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy(Cell Death and Disease, 2022) Hui, Ye; Chaobo, Chen; Hanghang, Wu; Kang, Zheng; Martín Adrados, Beatriz; Caparros, Esther; Francés, Rubén; Nelson, Leonard J.; Gómez Del Moral Martín-Consuegra, Manuel María; Asensio, Iris; Javier Vaquero; Bañares Cañizares, Rafael; Ávila, Matías A.; Andrade, Raúl J.; Lucena, María Isabel; Martínez Chantar, Maria Luz; Reeves, Helen L.; Masson, Steven; Blumberg, Richard S.; Gracia Sancho, Jordi; Nevzorova, Yulia; Martínez Naves, Eduardo; Cubero Palero, Francisco JavierAcetaminophen (APAP) hepatotoxicity induces endoplasmic reticulum (ER) stress which triggers the unfolded protein response (UPR) in hepatocytes. However, the mechanisms underlying ER stress remain poorly understood, thus reducing the options for exploring new pharmacological therapies for patients with hyperacute liver injury. Eight-to-twelve-week-old C57BL/6J Xbp1-floxed (Xbp1f/f) and hepatocyte-specific knockout Xbp1 mice (Xbp1∆hepa) were challenged with either high dose APAP [500 mg/kg] and sacrificed at early (1–2 h) and late (24 h) stages of hepatotoxicity. Histopathological examination of livers, immunofluorescence and immunohistochemistry, Western blot, real time (RT)-qPCR studies and transmission electron microscopy (TEM) were performed. Pharmacological inhibition of XBP1 using pre-treatment with STF-083010 [STF, 75 mg/kg] and autophagy induction with Rapamycin [RAPA, 8 mg/kg] or blockade with Chloroquine [CQ, 60 mg/kg] was also undertaken in vivo. Cytoplasmic expression of XBP1 coincided with severity of human and murine hyperacute liver injury. Transcriptional and translational activation of the UPR and sustained activation of JNK1/2 were major events in APAP hepatotoxicity, both in a human hepatocytic cell line and in a preclinical model. Xbp1∆hepa livers showed decreased UPR and JNK1/2 activation but enhanced autophagy in response to high dose APAP. Additionally, blockade of XBP1 splicing by STF, mitigated APAP-induced liver injury and without non-specific off-target effects (e.g., CYP2E1 activity). Furthermore, enhanced autophagy might be responsible for modulating CYP2E1 activity in Xbp1∆hepa animals. Genetic and pharmacological inhibition of Xbp1 specifically in hepatocytes ameliorated APAP-induced liver injury by enhancing autophagy and decreasing CYP2E1 expression. These findings provide the basis for the therapeutic restoration of ER stress and/or induction of autophagy in patients with hyperacute liver injury.Item Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy(Cell death diseases, 2022) Ye, Hui; Wu, Hanghang; Martín Adrados, Beatriz; Gómez Del Moral Martín-Consuegra, Manuel María; Bañares Cañizares, Rafael; Nevzorova, Yulia; Martínez Naves, Eduardo; Cubero Palero, Francisco JavierAcetaminophen (APAP) hepatotoxicity induces endoplasmic reticulum (ER) stress which triggers the unfolded protein response (UPR) in hepatocytes. However, the mechanisms underlying ER stress remain poorly understood, thus reducing the options for exploring new pharmacological therapies for patients with hyperacute liver injury. Eight-to-twelve-week-old C57BL/6J Xbp1-floxed (Xbp1f/f) and hepatocyte-specific knockout Xbp1 mice (Xbp1∆hepa) were challenged with either high dose APAP [500 mg/kg] and sacrificed at early (1-2 h) and late (24 h) stages of hepatotoxicity. Histopathological examination of livers, immunofluorescence and immunohistochemistry, Western blot, real time (RT)-qPCR studies and transmission electron microscopy (TEM) were performed. Pharmacological inhibition of XBP1 using pre-treatment with STF-083010 [STF, 75 mg/kg] and autophagy induction with Rapamycin [RAPA, 8 mg/kg] or blockade with Chloroquine [CQ, 60 mg/kg] was also undertaken in vivo. Cytoplasmic expression of XBP1 coincided with severity of human and murine hyperacute liver injury. Transcriptional and translational activation of the UPR and sustained activation of JNK1/2 were major events in APAP hepatotoxicity, both in a human hepatocytic cell line and in a preclinical model. Xbp1∆hepa livers showed decreased UPR and JNK1/2 activation but enhanced autophagy in response to high dose APAP. Additionally, blockade of XBP1 splicing by STF, mitigated APAP-induced liver injury and without non-specific off-target effects (e.g., CYP2E1 activity). Furthermore, enhanced autophagy might be responsible for modulating CYP2E1 activity in Xbp1∆hepa animals. Genetic and pharmacological inhibition of Xbp1 specifically in hepatocytes ameliorated APAP-induced liver injury by enhancing autophagy and decreasing CYP2E1 expression. These findings provide the basis for the therapeutic restoration of ER stress and/or induction of autophagy in patients with hyperacute liver injury.Item Intestinal Epithelial Cell-Derived Extracellular Vesicles Modulate Hepatic Injury via the Gut-Liver Axis During Acute Alcohol Injury(Frontiers in Pharmacology, 2020) Lamas Paz, Arantza; Morán, Laura; Salinas Rodríguez, Beatriz; López Alcántara, Nuria; Asensio, Iris; Fengjie, Hao; Kang, Zheng; Martín Adrados, Beatriz; Moreno Gutiérrez, Laura; Cogolludo Torralba, Ángel Luis; Gómez Del Moral Martín-Consuegra, Manuel María; Martínez Naves, Eduardo; Vaquero Martín, Francisco Javier; Bañares Cañizares, Rafael; Nevzorova, Yulia; Cubero Palero, Francisco JavierBinge drinking, i.e., heavy episodic drinking in a short time, has recently become an alarming societal problem with negative health impact. However, the harmful effects of acute alcohol injury in the gut-liver axis remain elusive. Hence, we focused on the physiological and pathological changes and the underlying mechanisms of experimental binge drinking in the context of the gut-liver axis. Eight-week-old mice with a C57BL/6 background received a single dose (p.o.) of ethanol (EtOH) [6 g/kg b.w.] as a preclinical model of acute alcohol injury. Controls received a single dose of PBS. Mice were sacrificed 8 h later. In parallel, HepaRGs and Caco-2 cells, human cell lines of differentiated hepatocytes and intestinal epithelial cells intestinal epithelial cells (IECs), respectively, were challenged in the presence or absence of EtOH [0-100 mM]. Extracellular vesicles (EVs) isolated by ultracentrifugation from culture media of IECs were added to hepatocyte cell cultures. Increased intestinal permeability, loss of zonula occludens-1 (ZO-1) and MUCIN-2 expression, and alterations in microbiota-increased Lactobacillus and decreased Lachnospiraceae species-were found in the large intestine of mice exposed to EtOH. Increased TUNEL-positive cells, infiltration of CD11b-positive immune cells, pro-inflammatory cytokines (e.g., tlr4, tnf, il1β), and markers of lipid accumulation (Oil Red O, srbep1) were evident in livers of mice exposed to EtOH, particularly in females. In vitro experiments indicated that EVs released by IECs in response to ethanol exerted a deleterious effect on hepatocyte viability and lipid accumulation. Overall, our data identified a novel mechanism responsible for driving hepatic injury in the gut-liver axis, opening novel avenues for therapyItem A Shortcut from Metabolic-Associated Fatty Liver Disease (MAFLD) to Hepatocellular Carcinoma (HCC): c-MYC a Promising Target for Preventative Strategies and Individualized Therapy(Cancers, 2021) Guo, Feifei; Estevez Vázquez, Olga; Benedé Ubieto, Raquel; Maya Mile, Douglas; Zheng, Kang; Gallego Durán, Rocío; Rojas Ávalos, Ángela; Ampuero, Javier; Romero Gómez, Manuel; Philip, Kaye; Egbuniwe, Isioma U.; Chen, Chaobo; Simon, Jorge; Delgado, Teresa C.; Martínez Chantar, Maria L.; Sun, Jie; Reissing, Johanna; Bruns, Tony; Lamas Paz, Arantza; Woitok, Marius Maximilian; Regueiro, José R.; Liedtke, Christian; Trautwein, Christian; Bañares Cañizares, Rafael; Cubero Palero, Francisco Javier; Benede Ubieto, Raquel; Gómez Del Moral Martín-Consuegra, Manuel María; Vaquero Martín, Francisco Javier; Nevzorova, YuliaBackground: Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC. Methods: alb-myctg mice were studied at baseline conditions and after administration of Western diet (WD) in comparison to WT littermates. c-MYC expression was analyzed in biopsies of patients with MAFLD and MAFLD-associated HCC by immunohistochemistry. Results: Mild obesity, spontaneous hyperlipidaemia, glucose intolerance and insulin resistance were characteristic of 36-week-old alb-myctg mice. Middle-aged alb-myctg exhibited liver steatosis and increased triglyceride content. Liver injury and inflammation were associated with elevated ALT, an upregulation of ER-stress response and increased ROS production, collagen deposition and compensatory proliferation. At 52 weeks, 20% of transgenic mice developed HCC. WD feeding exacerbated metabolic abnormalities, steatohepatitis, fibrogenesis and tumor prevalence. Therapeutic use of metformin partly attenuated the spontaneous MAFLD phenotype of alb-myctg mice. Importantly, upregulation and nuclear localization of c-MYC were characteristic of patients with MAFLD and MAFLD-related HCC. Conclusions: A novel function of c-MYC in MAFLD progression was identified opening new avenues for preventative strategies.Item Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis(Cell Death and Disease, 2023) Kang, Zheng; Fengjie, Hao; Medrano García, Sandra; Chaobo, Chen; Morán Blanco, Laura; Peligros Gómez, María Isabel; Bañares Cañizares, Rafael; Vaquero Martín, Francisco Javier; Gómez Del Moral Martín-Consuegra, Manuel María; Regueiro González-Barros, José Ramón; Martínez Naves, Eduardo; Gallego Durán, Rocío; Maya, Douglas; Ampuero, Javier; Romero Gómez, Manuel; Gilbert Ramos, Albert; Guixé Muntet, Sergi; Fernández Iglesias, Anabel; Gracia Sancho, Jordi; Coll, Mar; Graupera, Isabel; Ginès, Pere; Pericàs, Juan M.; Ramos Molina, Bruno; Herranz, José María; Ávila, Matías A.; Nevzorova, Yulia; Fernández Malavé, Edgar Gonzalo; Cubero Palero, Francisco JavierProgressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS-/-) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS-/- mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS-/- livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.