Aránzazu Sánchez

Universidad Complutense de Madrid

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Isabel Fabregat

Institut d'Investigació Biomédica de Bellvitge

Blanca Herrera

Hospital Clínico San Carlos

Cesáreo Roncero

Universidad Complutense de Madrid

Margarita Fernández

Pennsylvania State University

Manuel Benito

Universidad Complutense de Madrid

Annalisa Addante

Charité - Universitätsmedizin Berlin

AÁ

Alberto Álvarez

Universidad de Extremadura

ÁM

Ángela M. Valverde

Universidad Autónoma de Madrid

Valentina M. Factor

National Cancer Institute

Esther Bertrán

Institut d'Investigació Biomédica de Bellvitge

Cooperative Institutions

Universidad Complutense de Madrid

Heidelberg University

Instituto de Salud Carlos III

University Hospital Heidelberg

Universidad Autónoma de Madrid

Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

Consejo Superior de Investigaciones Científicas

University Medical Centre Mannheim

Centro de Investigación Biomédica en Red

Hospital Clínico San Carlos

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The rationale for targeting TGF‐β in chronic liver diseases

European Journal of Clinical Investigation (2016)

Gianluigi Giannelli Wolfgang Mikulits Steven Dooley Isabel Fabregat Aristidis Moustakas

Transforming growth factor (TGF)-β is a pluripotent cytokine that displays several tissue-specific biological activities. In the liver, TGF-β is considered a fundamental molecule, controlling organ size and growth by limiting hepatocyte proliferation. It is involved in fibrogenesis and, therefore, in worsening liver damage, as well as in triggering the development of hepatocellular carcinoma (HCC). TGF-β is known to act as an oncosuppressor and also as a tumour promoter in HCC, but its role is still unclear.In this review, we discuss the potential role of TGF-β in regulating the tumoural progression of HCC, and therefore the rationale for targeting this molecule in patients with HCC.A considerable amount of experimental preclinical evidence suggests that TGF-β is a promising druggable target in patients with HCC. To support this hypothesis, a phase II clinical trial is currently ongoing using a TGF-β pathway inhibitor, and results will soon be available.The identification of new TGF-β related biomarkers will help to select those patients most likely to benefit from therapy aimed at inhibiting the TGF-β pathway. New formulations that may provide a more controlled and sustained delivery of the drug will improve the therapeutic success of such treatments.

Druggability

10.1111/eci.12596

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Citations (65)

Relevance of epidermal growth factor receptor kinase activity in a model of cholestatic liver injury

Journal of Hepatology (2020)

Nerea Lazcanoiturburu Laura Almalé Rebeca Méndez Annalisa Addante Cesáreo Roncero

10.1016/s0168-8278(20)30912-0

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Citations (0)

264 NF-KB and STAT-3 are required for hepatic stem cell activation

Hepatology (2003)

Aránzazu Sánchez Péter Nagy Insa S. Schroeder Valentina M. Factor S.S. Thorgeirsson

10.1016/s0270-9139(03)80307-5

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Citations (1)

Autocrine production of TGF-β confers resistance to apoptosis after an epithelial–mesenchymal transition process in hepatocytes: Role of EGF receptor ligands

Experimental Cell Research (2006)

Gaelle del Castillo Miguel M. Murillo Alberto Álvarez Esther Bertrán Margarita Fernández

10.1016/j.yexcr.2006.05.017

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Citations (70)

Glucagon Regulation of Oxidative Phosphorylation Requires an Increase in Matrix Adenine Nucleotide Content through Ca2+ Activation of the Mitochondrial ATP-Mg/Pi Carrier SCaMC-3

Journal of Biological Chemistry (2013)

Ignácio Amigo Javier Traba M. Mar González‐Barroso Carlos B. Rueda Margarita Fernández

It has been known for a long time that mitochondria isolated from hepatocytes treated with glucagon or Ca2+-mobilizing agents such as phenylephrine show an increase in their adenine nucleotide (AdN) content, respiratory activity, and calcium retention capacity (CRC). Here, we have studied the role of SCaMC-3/slc25a23, the mitochondrial ATP-Mg/Pi carrier present in adult mouse liver, in the control of mitochondrial AdN levels and respiration in response to Ca2+ signals as a candidate target of glucagon actions. With the use of SCaMC-3 knock-out (KO) mice, we have found that the carrier is responsible for the accumulation of AdNs in liver mitochondria in a strictly Ca2+-dependent way with an S0.5 for Ca2+ activation of 3.3 ± 0.9 μm. Accumulation of matrix AdNs allows a SCaMC-3-dependent increase in CRC. In addition, SCaMC-3-dependent accumulation of AdNs is required to acquire a fully active state 3 respiration in AdN-depleted liver mitochondria, although further accumulation of AdNs is not followed by increases in respiration. Moreover, glucagon addition to isolated hepatocytes increases oligomycin-sensitive oxygen consumption and maximal respiratory rates in cells derived from wild type, but not SCaMC-3-KO mice and glucagon administration in vivo results in an increase in AdN content, state 3 respiration and CRC in liver mitochondria in wild type but not in SCaMC-3-KO mice. These results show that SCaMC-3 is required for the increase in oxidative phosphorylation observed in liver mitochondria in response to glucagon and Ca2+-mobilizing agents, possibly by allowing a Ca2+-dependent accumulation of mitochondrial AdNs and matrix Ca2+, events permissive for other glucagon actions. It has been known for a long time that mitochondria isolated from hepatocytes treated with glucagon or Ca2+-mobilizing agents such as phenylephrine show an increase in their adenine nucleotide (AdN) content, respiratory activity, and calcium retention capacity (CRC). Here, we have studied the role of SCaMC-3/slc25a23, the mitochondrial ATP-Mg/Pi carrier present in adult mouse liver, in the control of mitochondrial AdN levels and respiration in response to Ca2+ signals as a candidate target of glucagon actions. With the use of SCaMC-3 knock-out (KO) mice, we have found that the carrier is responsible for the accumulation of AdNs in liver mitochondria in a strictly Ca2+-dependent way with an S0.5 for Ca2+ activation of 3.3 ± 0.9 μm. Accumulation of matrix AdNs allows a SCaMC-3-dependent increase in CRC. In addition, SCaMC-3-dependent accumulation of AdNs is required to acquire a fully active state 3 respiration in AdN-depleted liver mitochondria, although further accumulation of AdNs is not followed by increases in respiration. Moreover, glucagon addition to isolated hepatocytes increases oligomycin-sensitive oxygen consumption and maximal respiratory rates in cells derived from wild type, but not SCaMC-3-KO mice and glucagon administration in vivo results in an increase in AdN content, state 3 respiration and CRC in liver mitochondria in wild type but not in SCaMC-3-KO mice. These results show that SCaMC-3 is required for the increase in oxidative phosphorylation observed in liver mitochondria in response to glucagon and Ca2+-mobilizing agents, possibly by allowing a Ca2+-dependent accumulation of mitochondrial AdNs and matrix Ca2+, events permissive for other glucagon actions.

Oligomycin

Adenine nucleotide

Mitochondrial matrix

Cellular respiration

10.1074/jbc.m112.409144

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Citations (50)

Polμ Deficiency Increases Resistance to Oxidative Damage and Delays Liver Aging

PLoS ONE (2014)

Beatriz Escudero Daniel Lucas Carmen Albó Suveera Dhup Jeff Bacher

Polμ is an error-prone PolX polymerase that contributes to classical NHEJ DNA repair. Mice lacking Polμ (Polμ−/−) show altered hematopoiesis homeostasis and DSB repair and a more pronounced nucleolytic resection of some V(D)J junctions. We previously showed that Polμ−/− mice have increased learning capacity at old ages, suggesting delayed brain aging. Here we investigated the effect of Polμ−/− deficiency on liver aging. We found that old Polμ−/− mice (>20 month) have greater liver regenerative capacity compared with wt animals. Old Polμ−/− liver showed reduced genomic instability and increased apoptosis resistance. However, Polμ−/− mice did not show an extended life span and other organs (e.g., heart) aged normally. Our results suggest that Polμ deficiency activates transcriptional networks that reduce constitutive apoptosis, leading to enhanced liver repair at old age.

Homeostasis

10.1371/journal.pone.0093074

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Citations (7)

Mean inner potentials of aluminium and copper

Journal of Physics C Solid State Physics (1983)

M. A. Ochando Aránzazu Sánchez C R Serna

Reflection high-energy electron diffraction patterns were taken from electropolished (100), (110) and (111) surfaces of aluminium and copper. From the displacements of the spots compared with the Bragg position the mean inner potentials were obtained, being 13.2 V for aluminium and 19.1 V for copper.

Reflection

Position (finance)

10.1088/0022-3719/16/13/001

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Citations (7)

Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis

Molecular Metabolism (2017)

Águeda González‐Rodríguez M. Pilar Valdecantos Patricia Rada Annalisa Addante Inés Barahona

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B), a negative modulator of insulin and cytokine signaling, is a therapeutic target for type 2 diabetes and obesity. We investigated the impact of PTP1B deficiency during NAFLD, particularly in non-alcoholic steatohepatitis (NASH).NASH features were evaluated in livers from wild-type (PTP1BWT) and PTP1B-deficient (PTP1BKO) mice fed methionine/choline-deficient diet (MCD) for 8 weeks. A recovery model was established by replacing MCD to chow diet (CHD) for 2-7 days. Non-parenchymal liver cells (NPCs) were analyzed by flow cytometry. Oval cells markers were measured in human and mouse livers with NASH, and in oval cells from PTP1BWT and PTP1BKO mice.PTP1BWT mice fed MCD for 8 weeks exhibited NASH, NPCs infiltration, and elevated Fgf21, Il6 and Il1b mRNAs. These parameters decreased after switching to CHD. PTP1B deficiency accelerated MCD-induced NASH. Conversely, after switching to CHD, PTP1BKO mice rapidly reverted NASH compared to PTP1BWT mice in parallel to the normalization of serum triglycerides (TG) levels. Among NPCs, a drop in cytotoxic natural killer T (NKT) subpopulation was detected in PTP1BKO livers during recovery, and in these conditions M2 macrophage markers were up-regulated. Oval cells markers (EpCAM and cytokeratin 19) significantly increased during NASH only in PTP1B-deficient livers. HGF-mediated signaling and proliferative capacity were enhanced in PTP1BKO oval cells. In NASH patients, oval cells markers were also elevated.PTP1B elicits a dual role in NASH progression and reversion. Additionally, our results support a new role for PTP1B in oval cell proliferation during NAFLD.

Steatohepatitis

10.1016/j.molmet.2017.10.008

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Citations (27)

Localización cromosómica y caracterización del polimorfismo del gen de la 2,4-dienoil-CoA reductasa (DECR) porcina

Alex Clop A. Cercós A. De la Torre Tomás Aránzazu Sánchez Marcel Amills

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IDF21-0272 Glycemic Variability in patients with SARS-CoV-2 admitted to the ICU

Diabetes Research and Clinical Practice (2022)

N. Capellan Juan Solozabal Echavarria Aránzazu Sánchez K. Disla D. Mejia

10.1016/j.diabres.2022.109328

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