Jordi Ribera

Hospital Clínic de Barcelona

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Manuel Morales‐Ruiz

Universitat de Barcelona

Wladimiro Jiménez

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

Gregori Casals

Universitat de Barcelona

Irene Portolés

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

M. Pauta

Hospital Clínic de Barcelona

Juan Rodríguez‐Vita

German Cancer Research Center

Guillermo Fernández–Varo

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Pedro Melgar‐Lesmes

Universitat de Barcelona

Loreto Boix

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

Denise Oró

Gubra (Denmark)

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Universitat de Barcelona

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

Hospital Clínic de Barcelona

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Instituto de Salud Carlos III

Centro de Investigación Biomédica en Red

Fundació Clínic per a la Recerca Biomèdica

Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer

Centre for Biomedical Network Research on Rare Diseases

Hospital Universitari de Vic

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Tcf20 deficiency is associated with increased liver fibrogenesis and alterations in mitochondrial metabolism in mice and humans

Liver International (2023)

Bernat Córdoba‐Jover Jordi Ribera Irene Portolés Elena Lecue Juan Rodríguez‐Vita

Abstract Background & Aims Transcription co‐activator factor 20 (TCF20) is a regulator of transcription factors involved in extracellular matrix remodelling. In addition, TCF20 genomic variants in humans have been associated with impaired intellectual disability. Therefore, we hypothesized that TCF20 has several functions beyond those described in neurogenesis, including the regulation of fibrogenesis. Methods Tcf20 knock‐out ( Tcf20 −/− ) and Tcf20 heterozygous mice were generated by homologous recombination. TCF20 gene genotyping and expression was assessed in patients with pathogenic variants in the TCF20 gene. Neural development was investigated by immufluorescense. Mitochondrial metabolic activity was evaluated with the Seahorse analyser. The proteome analysis was carried out by gas chromatography mass‐spectrometry. Results Characterization of Tcf20 −/− newborn mice showed impaired neural development and death after birth. In contrast, heterozygous mice were viable but showed higher CCl 4 ‐induced liver fibrosis and a differential expression of genes involved in extracellular matrix homeostasis compared to wild‐type mice, along with abnormal behavioural patterns compatible with autism‐like phenotypes. Tcf20 −/− embryonic livers and mouse embryonic fibroblast (MEF) cells revealed differential expression of structural proteins involved in the mitochondrial oxidative phosphorylation chain, increased rates of mitochondrial metabolic activity and alterations in metabolites of the citric acid cycle. These results parallel to those found in patients with TCF20 pathogenic variants, including alterations of the fibrosis scores (ELF and APRI) and the elevation of succinate concentration in plasma. Conclusions We demonstrated a new role of Tcf20 in fibrogenesis and mitochondria metabolism in mice and showed the association of TCF20 deficiency with fibrosis and metabolic biomarkers in humans.

10.1111/liv.15640

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Cerium Oxide Nanoparticles Protect against Oxidant Injury and Interfere with Oxidative Mediated Kinase Signaling in Human-Derived Hepatocytes

International Journal of Molecular Sciences (2019)

Silvia Carvajal Meritxell Perramón Gregori Casals Denise Oró Jordi Ribera

Cerium oxide nanoparticles (CeO2NPs) possess powerful antioxidant properties, thus emerging as a potential therapeutic tool in non-alcoholic fatty liver disease (NAFLD) progression, which is characterized by a high presence of reactive oxygen species (ROS). The aim of this study was to elucidate whether CeO2NPs can prevent or attenuate oxidant injury in the hepatic human cell line HepG2 and to investigate the mechanisms involved in this phenomenon. The effect of CeO2NPs on cell viability and ROS scavenging was determined, the differential expression of pro-inflammatory and oxidative stress-related genes was analyzed, and a proteomic analysis was performed to assess the impact of CeO2NPs on cell phosphorylation in human hepatic cells under oxidative stress conditions. CeO2NPs did not modify HepG2 cell viability in basal conditions but reduced H2O2- and lipopolysaccharide (LPS)-induced cell death and prevented H2O2-induced overexpression of MPO, PTGS1 and iNOS. Phosphoproteomic analysis showed that CeO2NPs reverted the H2O2-mediated increase in the phosphorylation of peptides related to cellular proliferation, stress response, and gene transcription regulation, and interfered with H2O2 effects on mTOR, MAPK/ERK, CK2A1 and PKACA signaling pathways. In conclusion, CeO2NPs protect HepG2 cells from cell-induced oxidative damage, reducing ROS generation and inflammatory gene expression as well as regulation of kinase-driven cell survival pathways.

Viability assay

10.3390/ijms20235959

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Citations (35)

Identification of Dhx15 as a Major Regulator of Liver Development, Regeneration and Tumor Growth in Zebrafish and Mice

Irene Portolés Jordi Ribera Esther Fernández‐Galán Elena Lecue Gregori Casals

Background: RNA helicase DHX15 plays a significant role in vasculature development and lung metastasis in vertebrates. In addition, several studies have demonstrated the overexpression of DHX15 in the context of hepatocellular carcinoma. Therefore, we hypothesized that this helicase may play a significant role in liver regeneration, physiology and pathology. Methods: Dhx15 gene deficiency was generated by CRISPR/Cas9 in zebrafish and by TALEN-RNA in mice. FANA Antisense-Oligonucleotides were used to silence Dhx15 in wild-type mice. The hepatocellular carcinoma tumor induction model was generated by subcutaneous injection of Hepa 1-6 cells. Results: Homozygous Dhx15 gene deficiency was lethal in zebrafish and mouse embryos. Dhx15 gene deficiency impaired liver organogenesis in zebrafish embryos and liver regeneration after partial hepatectomy in mice. Also, heterozygous mice presented decreased number and size of liver metastasis after Hepa 1-6 cells injection compared to wild-type mice. Dhx15 gene silencing with FANA Antisense-Oligonucleotides in wild-type mice resulted in 80% reduced expression in the liver and a significant reduction in other major organs. In addition, Dhx15 gene silencing significantly hindered primary tumor growth in the hepatocellular carcinoma experimental model. Regarding the potential use of DHX15 as a diagnostic marker for liver disease, patients with hepatocellular carcinoma showed increased levels of DHX15 in blood samples compared with subjects without hepatic affectation. Conclusion: Dhx15 is a key regulator of liver physiology and organogenesis, is increased in the blood of cirrhotic and hepatocellular carcinoma patients and has a key role in controlling hepatocellular carcinoma tumor growth and expansion in experimental models.

Liver Regeneration

Liver Cancer

10.20944/preprints202401.0766.v1

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Cerium oxide nanoparticles improve liver regeneration after acetaminophen-induced liver injury and partial hepatectomy in rats

Journal of Nanobiotechnology (2019)

Bernat Córdoba‐Jover Altamira Arce-Cerezo Jordi Ribera M. Pauta Denise Oró

Cerium oxide nanoparticles are effective scavengers of reactive oxygen species and have been proposed as a treatment for oxidative stress-related diseases. Consequently, we aimed to investigate the effect of these nanoparticles on hepatic regeneration after liver injury by partial hepatectomy and acetaminophen overdose.All the in vitro experiments were performed in HepG2 cells. For the acetaminophen and partial hepatectomy experimental models, male Wistar rats were divided into three groups: (1) nanoparticles group, which received 0.1 mg/kg cerium nanoparticles i.v. twice a week for 2 weeks before 1 g/kg acetaminophen treatment, (2) N-acetyl-cysteine group, which received 300 mg/kg of N-acetyl-cysteine i.p. 1 h after APAP treatment and (3) partial hepatectomy group, which received the same nanoparticles treatment before partial hepatectomy. Each group was matched with vehicle-controlled rats.In the partial hepatectomy model, rats treated with cerium oxide nanoparticles showed a significant increase in liver regeneration, compared with control rats. In the acetaminophen experimental model, nanoparticles and N-acetyl-cysteine treatments decreased early liver damage in hepatic tissue. However, only the effect of cerium oxide nanoparticles was associated with a significant increment in hepatocellular proliferation. This treatment also reduced stress markers and increased cell cycle progression in hepatocytes and the activation of the transcription factor NF-κB in vitro and in vivo.Our results demonstrate that the nanomaterial cerium oxide, besides their known antioxidant capacities, can enhance hepatocellular proliferation in experimental models of liver regeneration and drug-induced hepatotoxicity.

Acetaminophen

Liver Regeneration

Cerium oxide

10.1186/s12951-019-0544-5

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Citations (51)

Treatment of Hepatic Fibrosis in Mice Based on Targeted Plasmonic Hyperthermia

ACS Nano (2021)

Jordi Ribera Clara Vilches Vanesa Sanz Ignacio de Miguel Irene Portolés

Liver fibrosis is a major health problem with multiple associated complications, which, to date, has no effective treatment. Hepatic stellate cells are the main responsible cells for fibrosis formation; upon their activation, excess accumulation of extracellular matrix and collagen deposits occurs. The mitogen platelet-derived growth factor (PDGF) and its receptor β (PDGFRβ) play a major role in hepatic stellate cells activation and are, therefore, promising targets for antifibrotic therapies. Gold nanorods hold great potential for diseased liver treatments, since their passive hepatic accumulation enhances active targeting strategies, hence increasing therapeutic efficiency. In addition, gold nanorods have photothermal properties that, combined with specific cell delivery, can be exploited to induce localized near-infrared light-mediated thermal ablation. Here, we demonstrate that gold nanorods coated with anti-PDGFRβ specifically target activated hepatic stellate cells in vivo. Additionally, gold nanorods-PDGFRβ-mediated photothermal therapy decreases fibrosis, hepatic inflammation, and hepatocyte injury in the experimental model of CCl4-induced liver fibrosis in mice.

Hepatic stellate cell

Hepatic fibrosis

Nanorod

10.1021/acsnano.1c00988

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Graphene–Dendrimer Nanostars for Targeted Macrophage Overexpression of Metalloproteinase 9 and Hepatic Fibrosis Precision Therapy

Nano Letters (2018)

Pedro Melgar‐Lesmes Aureli Luquero Marina Parra‐Robert Adriana Mora Jordi Ribera

Fibrosis contributes to ∼45% of all deaths in industrialized nations, but no direct antifibrotic therapeutic interventions exist to date. Graphene-based nanomaterials exhibit excellent versatility in electronics, and emerging trends exploit their properties for biomedical applications, especially for drug and gene delivery. We designed constructs of graphene nanostars linked to PAMAM-G5 dendrimer for the selective targeting and delivery of a plasmid expressing the collagenase metalloproteinase 9 under the CD11b promoter into inflammatory macrophages in cirrhotic livers. Graphene nanostars preferentially accumulated in inflammatory macrophages M1 in less than 3 h in a manner unaffected by covalent linkage to dendrimers. Dendrimer-graphene nanostars efficiently delivered the plasmid encoding for metalloproteinase 9 into macrophages, allowing the synthesis and secretion of the metalloproteinase to digest adjacent collagen fibers. In turn, metalloproteinase 9 overexpression promoted the macrophage switch from inflammatory M1 to pro-regenerative M2 in 3 days. This targeted gene therapy reduced selectively and locally the presence of collagen fibers in fibrotic tracts where inflammatory macrophages accumulated in cirrhotic mice without affecting the activation state of hepatic stellate cells. Overall, this treatment significantly reduced hepatic injury and improved liver restoration in mice with liver cirrhosis treated for 10 days. Graphene-dendrimer nanostars targeted the macrophage overexpression of metalloproteinase 9, selectively reducing hepatic fibrosis, and might be a good treatment for diseases associated with fibrosis and inflammatory macrophage accumulation.

Hepatic stellate cell

10.1021/acs.nanolett.8b02498

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Citations (49)

Increased nitric oxide production in lymphatic endothelial cells causes impairment of lymphatic drainage in cirrhotic rats

Gut (2012)

Jordi Ribera M. Pauta Pedro Melgar‐Lesmes Sònia Tugues Guillermo Fernández–Varo

Background and aim

The lymphatic network plays a major role in maintaining tissue fluid homoeostasis. Therefore several pathological conditions associated with oedema formation result in deficient lymphatic function. However, the role of the lymphatic system in the pathogenesis of ascites and oedema formation in cirrhosis has not been fully clarified. The aim of this study was to investigate whether the inability of the lymphatic system to drain tissue exudate contributes to the oedema observed in cirrhosis.

Methods

Cirrhosis was induced in rats by CCl₄ inhalation. Lymphatic drainage was evaluated using fluorescent lymphangiography. Expression of endothelial nitric oxide synthase (eNOS) was measured in primary lymphatic endothelial cells (LyECs). Inhibition of eNOS activity in cirrhotic rats with ascites (CH) was carried out by L-N^G-methyl-L-arginine (L-NMMA) treatment (0.5 mg/kg/day).

Results

The (CH) rats had impaired lymphatic drainage in the splanchnic and peripheral regions compared with the control (CT) rats. LyECs isolated from the CH rats showed a significant increase in eNOS and nitric oxide (NO) production. In addition, the lymphatic vessels of the CH rats showed a significant reduction in smooth muscle cell (SMC) coverage compared with the CT rats. CH rats treated with L-NMMA for 7 days showed a significant improvement in lymphatic drainage and a significant reduction in ascites volume, which were associated with increased plasma volume. This beneficial effect of L-NMMA inhibition was also associated with a significant increase in lymphatic SMC coverage.

Conclusions

The upregulation of eNOS in the LyECs of CH rats causes long-term lymphatic remodelling, which is characterised by a loss of SMC lymphatic coverage. The amelioration of this lymphatic abnormality by chronic eNOS inhibition results in improved lymphatic drainage and reduced ascites.

Lymphatic Endothelium

Lymphatic vessel

Lymphatic disease

10.1136/gutjnl-2011-300703

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Citations (54)

The loss of DHX15 impairs endothelial energy metabolism, lymphatic drainage and tumor metastasis in mice

Communications Biology (2021)

Jordi Ribera Irene Portolés Bernat Córdoba‐Jover Juan Rodríguez‐Vita Gregori Casals

Abstract DHX15 is a downstream substrate for Akt1, which is involved in key cellular processes affecting vascular biology. Here, we explored the vascular regulatory function of DHX15. Homozygous DHX15 gene deficiency was lethal in mouse and zebrafish embryos. DHX15 —/— zebrafish also showed downregulation of VEGF-C and reduced formation of lymphatic structures during development. DHX15 +/− mice depicted lower vascular density and impaired lymphatic function postnatally. RNAseq and proteome analysis of DHX15 silenced endothelial cells revealed differential expression of genes involved in the metabolism of ATP biosynthesis. The validation of these results demonstrated a lower activity of the Complex I in the mitochondrial membrane of endothelial cells, resulting in lower intracellular ATP production and lower oxygen consumption. After injection of syngeneic LLC1 tumor cells, DHX15 +/− mice showed partially inhibited primary tumor growth and reduced lung metastasis. Our results revealed an important role of DHX15 in vascular physiology and pave a new way to explore its potential use as a therapeutical target for metastasis treatment.

Lymphatic Endothelium

10.1038/s42003-021-02722-w

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Citations (8)

Identification of Dhx15 as a Major Regulator of Liver Development, Regeneration, and Tumor Growth in Zebrafish and Mice

International Journal of Molecular Sciences (2024)

Irene Portolés Jordi Ribera Esther Fernández‐Galán Elena Lecue Gregori Casals

RNA helicase DHX15 plays a significant role in vasculature development and lung metastasis in vertebrates. In addition, several studies have demonstrated the overexpression of DHX15 in the context of hepatocellular carcinoma. Therefore, we hypothesized that this helicase may play a significant role in liver regeneration, physiology, and pathology. Dhx15 gene deficiency was generated by CRISPR/Cas9 in zebrafish and by TALEN-RNA in mice. AUM Antisense-Oligonucleotides were used to silence Dhx15 in wild-type mice. The hepatocellular carcinoma tumor induction model was generated by subcutaneous injection of Hepa 1-6 cells. Homozygous Dhx15 gene deficiency was lethal in zebrafish and mouse embryos. Dhx15 gene deficiency impaired liver organogenesis in zebrafish embryos and liver regeneration after partial hepatectomy in mice. Also, heterozygous mice presented decreased number and size of liver metastasis after Hepa 1-6 cells injection compared to wild-type mice. Dhx15 gene silencing with AUM Antisense-Oligonucleotides in wild-type mice resulted in 80% reduced expression in the liver and a significant reduction in other major organs. In addition, Dhx15 gene silencing significantly hindered primary tumor growth in the hepatocellular carcinoma experimental model. Regarding the potential use of DHX15 as a diagnostic marker for liver disease, patients with hepatocellular carcinoma showed increased levels of DHX15 in blood samples compared with subjects without hepatic affectation. In conclusion, Dhx15 is a key regulator of liver physiology and organogenesis, is increased in the blood of cirrhotic and hepatocellular carcinoma patients, and plays a key role in controlling hepatocellular carcinoma tumor growth and expansion in experimental models.

Liver Regeneration

Liver Cancer

10.3390/ijms25073716

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Liver FoxO1 overexpression is positively associated with the degree of liver injury in cirrhotic patients

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Esther Fernández‐Galán Silvia Sandalinas Blai Morales‐Romero Laura Macías‐Muñoz M. Pauta

ABSTRACT Introduction Chronic liver disease is associated with high mortality. Liver transplantation is the definitive treatment for patients with end-stage liver disease, improving their survival and quality of life. However, chronic rejection of the graft and the imbalance between the demand and the availability of organs limit its applicability. Therefore, finding therapeutic and/or diagnostic alternatives for these patients is a priority. In this context, preclinical studies in rodents have demonstrated that Akt plays a key role in liver dysfunction. Even with all this evidence, the activation status of Akt and its downstream targets in the liver of patients with chronic hepatopathy is still unknown. Hence, the present study aims to determine the activation status of the molecules involved in the Akt signaling pathway in livers of cirrhotic patients. Materials and Methods In this study, 36 liver tissue samples from a cohort of 27 cirrhotic patients and 9 patients without cirrhosis were included. A total of 10 proteins involved in Akt/mTOR pathway (GSK3β, IGF1R, IRS1, mTOR, p70S6K, IR, PTEN, GSK3α, TSC2, and RPS6) were analyzed using a multiplex immunoassay based on Luminex® technology. Results Significant differences were found in several Akt/mTOR target proteins between the groups of cirrhotic patients vs. non-cirrhotic: FoxO1 (9.5 vs. 4.4; p <0.01), p-Akt (2.1 vs. 1.0; p <0.01), PTEN (3.061 vs. 1.877; p <0.05) and p70S6K (196.3 vs. 270.5; p <0.001). FoxO1 showed the best correlation with biochemical markers of liver injury aspartate aminotransferase and serum alanine aminotransferase (ASAT: r=0.51, p <0.05; ALAT: r=0.49, p <0.05). Moreover, the individual influence of FoxO1 on these parameters was confirmed by multiple regression analysis. It was the only enzyme in the Akt signaling pathway identified as a positive independent predictor of increased ASAT and ALAT levels. Conclusion FoxO1 is overexpressed in the liver of cirrhotic patients after partial hepatectomy. FoxO1 levels are also associated with the degree of liver injury, showing a positive correlation with current biomarkers used in clinical practice to detect liver injury.

Chronic liver disease

Liver disease

FOXO1

10.1101/2020.11.05.369504

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Citations (1)