Publications by authors named "Carmen Berasain"

85 Publications

The splicing regulator SLU7 is required to preserve DNMT1 protein stability and DNA methylation.

Nucleic Acids Res 2021 Sep;49(15):8592-8609

Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona 31008, Spain.

Gene expression is finely and dynamically controlled through the tightly coordinated and interconnected activity of epigenetic modulators, transcription and splicing factors and post-translational modifiers. We have recently identified the splicing factor SLU7 as essential for maintaining liver cell identity and genome integrity and for securing cell division both trough transcriptional and splicing mechanisms. Now we uncover a new function of SLU7 controlling gene expression at the epigenetic level. We show that SLU7 is required to secure DNMT1 protein stability and a correct DNA methylation. We demonstrate that SLU7 is part in the chromatome of the protein complex implicated in DNA methylation maintenance interacting with and controlling the integrity of DNMT1, its adaptor protein UHRF1 and the histone methyl-transferase G9a at the chromatin level. Mechanistically, we found that SLU7 assures DNMT1 stability preventing its acetylation and degradation by facilitating its interaction with HDAC1 and the desubiquitinase USP7. Importantly, we demonstrate that this DNMT1 dependency on SLU7 occurs in a large panel of proliferating cell lines of different origins and in in vivo models of liver proliferation. Overall, our results uncover a novel and non-redundant role of SLU7 in DNA methylation and present SLU7 as a holistic regulator of gene expression.
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http://dx.doi.org/10.1093/nar/gkab649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421144PMC
September 2021

Next-generation sequencing of bile cell-free DNA for the early detection of patients with malignant biliary strictures.

Gut 2021 Jul 20. Epub 2021 Jul 20.

Navarra Institute for Health Research, IdiSNA, Pamplona, Spain.

Objective: Despite significant progresses in imaging and pathological evaluation, early differentiation between benign and malignant biliary strictures remains challenging. Endoscopic retrograde cholangiopancreatography (ERCP) is used to investigate biliary strictures, enabling the collection of bile. We tested the diagnostic potential of next-generation sequencing (NGS) mutational analysis of bile cell-free DNA (cfDNA).

Design: A prospective cohort of patients with suspicious biliary strictures (n=68) was studied. The performance of initial pathological diagnosis was compared with that of the mutational analysis of bile cfDNA collected at the time of first ERCP using an NGS panel open to clinical laboratory implementation, the Oncomine Pan-Cancer Cell-Free assay.

Results: An initial pathological diagnosis classified these strictures as of benign (n=26), indeterminate (n=9) or malignant (n=33) origin. Sensitivity and specificity of this diagnosis were 60% and 100%, respectively, as on follow-up 14 of the 26 and eight of the nine initially benign or indeterminate strictures resulted malignant. Sensitivity and specificity for malignancy of our NGS assay, herein named Bilemut, were 96.4% and 69.2%, respectively. Importantly, one of the four Bilemut false positives developed pancreatic cancer after extended follow-up. Remarkably, the sensitivity for malignancy of Bilemut was 100% in patients with an initial diagnosis of benign or indeterminate strictures. Analysis of 30 paired bile and tissue samples also demonstrated the superior performance of Bilemut.

Conclusion: Implementation of Bilemut at the initial diagnostic stage for biliary strictures can significantly improve detection of malignancy, reduce delays in the clinical management of patients and assist in selecting patients for targeted therapies.
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http://dx.doi.org/10.1136/gutjnl-2021-325178DOI Listing
July 2021

Splicing Factor SLU7 Prevents Oxidative Stress-Mediated Hepatocyte Nuclear Factor 4α Degradation, Preserving Hepatic Differentiation and Protecting From Liver Damage.

Hepatology 2021 Jun 25. Epub 2021 Jun 25.

Hepatology Program, CIMA, University of Navarra, Pamplona, Spain.

Background And Aims: Hepatocellular dedifferentiation is emerging as an important determinant in liver disease progression. Preservation of mature hepatocyte identity relies on a set of key genes, predominantly the transcription factor hepatocyte nuclear factor 4α (HNF4α) but also splicing factors like SLU7. How these factors interact and become dysregulated and the impact of their impairment in driving liver disease are not fully understood.

Approach And Results: Expression of SLU7 and that of the adult and oncofetal isoforms of HNF4α, driven by its promoter 1 (P1) and P2, respectively, was studied in diseased human and mouse livers. Hepatic function and damage response were analyzed in wild-type and Slu7-haploinsufficient/heterozygous (Slu7 ) mice undergoing chronic (CCl ) and acute (acetaminophen) injury. SLU7 expression was restored in CCl -injured mice using SLU7-expressing adeno-associated viruses (AAV-SLU7). The hepatocellular SLU7 interactome was characterized by mass spectrometry. Reduced SLU7 expression in human and mouse diseased livers correlated with a switch in HNF4α P1 to P2 usage. This response was reproduced in Slu7 mice, which displayed increased sensitivity to chronic and acute liver injury, enhanced oxidative stress, and marked impairment of hepatic functions. AAV-SLU7 infection prevented liver injury and hepatocellular dedifferentiation. Mechanistically we demonstrate a unique role for SLU7 in the preservation of HNF4α1 protein stability through its capacity to protect the liver against oxidative stress. SLU7 is herein identified as a key component of the stress granule proteome, an essential part of the cell's antioxidant machinery.

Conclusions: Our results place SLU7 at the highest level of hepatocellular identity control, identifying SLU7 as a link between stress-protective mechanisms and liver differentiation. These findings emphasize the importance of the preservation of hepatic functions in the protection from liver injury.
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http://dx.doi.org/10.1002/hep.32029DOI Listing
June 2021

lncRNA regulates Myc translation in hepatocellular carcinoma via sequestering TIAR.

Elife 2021 May 18;10. Epub 2021 May 18.

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.

Hepatocellular carcinoma, the most common type of liver malignancy, is one of the most lethal forms of cancer. We identified a long non-coding RNA, , that is overexpressed in hepatocellular carcinoma and mouse embryonic stem cells. We named this RNA , or . Depletion of impacts cell proliferation and migration, which can be rescued by ectopic expression of . RNA-seq analysis of knockouts revealed that a large number of genes with decreased expression contain a motif in their promoter. MYC is decreased in knockout cells at the protein level, but not the mRNA level. RNA-antisense pulldown identified nucleolysin TIAR, a translational repressor, to bind to a 71-nt hairpin within , sequestration of which increases MYC translation. In summary, our data suggest that regulates MYC translation by sequestering TIAR and as such represents a potentially exciting diagnostic or therapeutic target in hepatocellular carcinoma.
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http://dx.doi.org/10.7554/eLife.68263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163507PMC
May 2021

Epigenetic Biomarkers for the Diagnosis and Treatment of Liver Disease.

Cancers (Basel) 2021 Mar 12;13(6). Epub 2021 Mar 12.

Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.

Research in the last decades has demonstrated the relevance of epigenetics in controlling gene expression to maintain cell homeostasis, and the important role played by epigenome alterations in disease development. Moreover, the reversibility of epigenetic marks can be harnessed as a therapeutic strategy, and epigenetic marks can be used as diagnosis biomarkers. Epigenetic alterations in DNA methylation, histone post-translational modifications (PTMs), and non-coding RNA (ncRNA) expression have been associated with the process of hepatocarcinogenesis. Here, we summarize epigenetic alterations involved in the pathogenesis of chronic liver disease (CLD), particularly focusing on DNA methylation. We also discuss their utility as epigenetic biomarkers in liquid biopsy for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Finally, we discuss the potential of epigenetic therapeutic strategies for HCC treatment.
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http://dx.doi.org/10.3390/cancers13061265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998165PMC
March 2021

ARMCX3 Mediates Susceptibility to Hepatic Tumorigenesis Promoted by Dietary Lipotoxicity.

Cancers (Basel) 2021 Mar 5;13(5). Epub 2021 Mar 5.

Department of Biochemistry and Molecular Biomedicine and Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain.

ARMCX3 is encoded by a member of the Armcx gene family and is known to be involved in nervous system development and function. We found that ARMCX3 is markedly upregulated in mouse liver in response to high lipid availability, and that hepatic ARMCX3 is upregulated in patients with NAFLD and hepatocellular carcinoma (HCC). Mice were subjected to ARMCX3 invalidation (inducible ARMCX3 knockout) and then exposed to a high-fat diet and diethylnitrosamine-induced hepatocarcinogenesis. The effects of experimental ARMCX3 knockdown or overexpression in HCC cell lines were also analyzed. ARMCX3 invalidation protected mice against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis. ARMCX3 invalidation promoted apoptotic cell death and macrophage infiltration in livers of diethylnitrosamine-treated mice maintained on a high-fat diet. ARMCX3 downregulation reduced the viability, clonality and migration of HCC cell lines, whereas ARMCX3 overexpression caused the reciprocal effects. SOX9 was found to mediate the effects of ARMCX3 in hepatic cells, with the SOX9 interaction required for the effects of ARMCX3 on hepatic cell proliferation. In conclusion, ARMCX3 is identified as a novel molecular actor in liver physiopathology and carcinogenesis. ARMCX3 downregulation appears to protect against hepatocarcinogenesis, especially under conditions of high dietary lipid-mediated hepatic insult.
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http://dx.doi.org/10.3390/cancers13051110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961652PMC
March 2021

Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis.

Cancers (Basel) 2020 Dec 13;12(12). Epub 2020 Dec 13.

Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.

Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated -KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor β (TGFβ). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strategy.
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http://dx.doi.org/10.3390/cancers12123748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763137PMC
December 2020

Dual Targeting of G9a and DNA Methyltransferase-1 for the Treatment of Experimental Cholangiocarcinoma.

Hepatology 2021 Jun;73(6):2380-2396

Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain.

Background And Aims: Cholangiocarcinoma (CCA) is a devastating disease often detected at advanced stages when surgery cannot be performed. Conventional and targeted systemic therapies perform poorly, and therefore effective drugs are urgently needed. Different epigenetic modifications occur in CCA and contribute to malignancy. Targeting epigenetic mechanisms may thus open therapeutic opportunities. However, modifications such as DNA and histone methylation often coexist and cooperate in carcinogenesis. We tested the therapeutic efficacy and mechanism of action of a class of dual G9a histone-methyltransferase and DNA-methyltransferase 1 (DNMT1) inhibitors.

Approach And Results: Expression of G9a, DNMT1, and their molecular adaptor, ubiquitin-like with PHD and RING finger domains-1 (UHRF1), was determined in human CCA. We evaluated the effect of individual and combined pharmacological inhibition of G9a and DNMT1 on CCA cell growth. Our lead G9a/DNMT1 inhibitor, CM272, was tested in human CCA cells, patient-derived tumoroids and xenograft, and a mouse model of cholangiocarcinogenesis with hepatocellular deletion of c-Jun-N-terminal-kinase (Jnk)-1/2 and diethyl-nitrosamine (DEN) plus CCl treatment (Jnk + DEN + CCl mice). We found an increased and correlative expression of G9a, DNMT1, and UHRF1 in CCAs. Cotreatment with independent pharmacological inhibitors G9a and DNMT1 synergistically inhibited CCA cell growth. CM272 markedly reduced CCA cell proliferation and synergized with Cisplatin and the ERBB-targeted inhibitor, Lapatinib. CM272 inhibited CCA tumoroids and xenograft growth and significantly antagonized CCA progression in Jnk + DEN + CCl mice without apparent toxicity. Mechanistically, CM272 reprogrammed the tumoral metabolic transcriptome and phenotype toward a differentiated and quiescent status.

Conclusions: Dual targeting of G9a and DNMT1 with epigenetic small molecule inhibitors such as CM272 is a potential strategy to treat CCA and/or enhance the efficacy of other systemic therapies.
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http://dx.doi.org/10.1002/hep.31642DOI Listing
June 2021

FGF15/19 is required for adipose tissue plasticity in response to thermogenic adaptations.

Mol Metab 2021 01 7;43:101113. Epub 2020 Nov 7.

Department of Biochemistry and Molecular Biomedicine and Institute of Biomedicine, University of Barcelona, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain; CIBEROBN, Carlos III Health Institute, Spain. Electronic address:

Objective: To determine the role of enterokine FGF15/19 in adipose tissue thermogenic adaptations.

Methods: Circulating FGF19 and gene expression (qRT-PCR) levels were assessed in subcutaneous adipose tissue from obese human patients. Effects of experimentally increased FGF15 and FGF19 levels in vivo were determined in mice using adenoviral and adeno-associated vectors. Adipose tissues were characterized in FGF15-null mice under distinct cold-related thermogenic challenges. The analyses spanned metabolic profiling, tissue characterization, histology, gene expression, and immunoblot assays.

Results: In humans, FGF19 levels are directly associated with UCP1 gene expression in subcutaneous adipose tissue. Experimental increases in FGF15 or FGF19 induced white fat browning in mice as demonstrated by the appearance of multilocular beige cells and markers indicative of a beige phenotype, including increased UCP1 protein levels. Mice lacking FGF15 showed markedly impaired white adipose tissue browning and a mild reduction in parameters indicative of BAT activity in response to cold-induced environmental thermogenic challenges. This was concomitant with signs of altered systemic metabolism, such as reduced glucose tolerance and impaired cold-induced insulin sensitization.

Conclusions: Enterokine FGF15/19 is a key factor required for adipose tissue plasticity in response to thermogenic adaptations.
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http://dx.doi.org/10.1016/j.molmet.2020.101113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691747PMC
January 2021

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg.

JHEP Rep 2020 Dec 7;2(6):100167. Epub 2020 Aug 7.

Hepatology Program CIMA, University of Navarra, Pamplona, Spain.

Hepatocellular carcinoma (HCC) is a deadly tumour whose causative agents are generally well known, but whose pathogenesis remains poorly understood. Nevertheless, key genetic alterations are emerging from a heterogeneous molecular landscape, providing information on the tumorigenic process from initiation to progression. Among these molecular alterations, those that affect epigenetic processes are increasingly recognised as contributing to carcinogenesis from preneoplastic stages. The epigenetic machinery regulates gene expression through intertwined and partially characterised circuits involving chromatin remodelers, covalent DNA and histone modifications, and dedicated proteins reading these modifications. In this review, we summarise recent findings on HCC epigenetics, focusing mainly on changes in DNA and histone modifications and their carcinogenic implications. We also discuss the potential drugs that target epigenetic mechanisms for HCC treatment, either alone or in combination with current therapies, including immunotherapies.
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http://dx.doi.org/10.1016/j.jhepr.2020.100167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585149PMC
December 2020

Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?

Cells 2020 10 19;9(10). Epub 2020 Oct 19.

Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.

Chronic liver diseases (CLD) represent a worldwide health problem. While CLDs may have diverse etiologies, a common pathogenic denominator is the presence of liver fibrosis. Cirrhosis, the end-stage of CLD, is characterized by extensive fibrosis and is markedly associated with the development of hepatocellular carcinoma. The most important event in hepatic fibrogenesis is the activation of hepatic stellate cells (HSC) following liver injury. Activated HSCs acquire a myofibroblast-like phenotype becoming proliferative, fibrogenic, and contractile cells. While transient activation of HSCs is part of the physiological mechanisms of tissue repair, protracted activation of a wound healing reaction leads to organ fibrosis. The phenotypic changes of activated HSCs involve epigenetic mechanisms mediated by non-coding RNAs (ncRNA) as well as by changes in DNA methylation and histone modifications. During CLD these epigenetic mechanisms become deregulated, with alterations in the expression and activity of epigenetic modulators. Here we provide an overview of the epigenetic alterations involved in fibrogenic HSCs transdifferentiation with particular focus on histones acetylation changes. We also discuss recent studies supporting the promising therapeutic potential of histone deacetylase inhibitors in liver fibrosis.
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http://dx.doi.org/10.3390/cells9102321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589994PMC
October 2020

Vitamin A in Nonalcoholic Fatty Liver Disease: A Key Player in an Offside Position?

Cell Mol Gastroenterol Hepatol 2021 21;11(1):291-293. Epub 2020 Sep 21.

Hepatology Program, CIMA, University of Navarra, Pamplona, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases, (CIBERehd, Carlos III Health Institute), Madrid, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.jcmgh.2020.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768560PMC
July 2021

Epigenetic Mechanisms in Gastric Cancer: Potential New Therapeutic Opportunities.

Int J Mol Sci 2020 Jul 31;21(15). Epub 2020 Jul 31.

Program of Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.

Gastric cancer (GC) is one of the deadliest malignancies worldwide. Complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. Besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer onset and progression, representing a hallmark of gastric malignancies. Moreover, epigenetic mechanisms undergo an intricate crosstalk, and distinct epigenomic profiles can be shaped under different microenvironmental contexts. In this scenario, targeting epigenetic mechanisms could be an interesting therapeutic strategy to overcome gastric cancer heterogeneity, and the efforts conducted to date are delivering promising results. In this review, we summarize the key epigenetic events involved in gastric cancer development. We conclude with a discussion of new promising epigenetic strategies for gastric cancer treatment.
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http://dx.doi.org/10.3390/ijms21155500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432799PMC
July 2020

Amphiregulin Aggravates Glomerulonephritis Recruitment and Activation of Myeloid Cells.

J Am Soc Nephrol 2020 09 2;31(9):1996-2012. Epub 2020 Jul 2.

III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Background: Recent studies have identified the EGF receptor (EGFR) ligand amphiregulin (AREG) as an important mediator of inflammatory diseases. Both pro- and anti-inflammatory functions have been described, but the role of AREG in GN remains unknown.

Methods: The nephrotoxic nephritis model of GN was studied in AREG mice after bone marrow transplantation, and in mice with myeloid cell-specific EGFR deficiency. Therapeutic utility of AREG neutralization was assessed. Furthermore, AREG's effects on renal cells and monocytes/macrophages (M/M) were analyzed. Finally, we evaluated AREG expression in human renal biopsies.

Results: Renal AREG mRNA was strongly upregulated in murine GN. Renal resident cells were the most functionally relevant source of AREG. Importantly, the observation that knockout mice showed significant amelioration of disease indicates that AREG is pathogenic in GN. AREG enhanced myeloid cell responses inducing chemokine and colony stimulating factor 2 (CSF2) expression in kidney resident cells. Furthermore, AREG directly skewed M/M to a proinflammatory M1 phenotype and protected them from apoptosis. Consequently, anti-AREG antibody treatment dose-dependently ameliorated GN. Notably, selective abrogation of EGFR signaling in myeloid cells was sufficient to protect against nephritis. Finally, strong upregulation of AREG expression was also detected in kidneys of patients with two forms of crescentic GN.

Conclusions: AREG is a proinflammatory mediator of GN () enhancing renal pathogenic myeloid cell infiltration and () direct effects on M/M polarization, proliferation, and cytokine secretion. The AREG/EGFR axis is a potential therapeutic target for acute GN.
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http://dx.doi.org/10.1681/ASN.2019111215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461677PMC
September 2020

Pilot Multi-Omic Analysis of Human Bile from Benign and Malignant Biliary Strictures: A Machine-Learning Approach.

Cancers (Basel) 2020 Jun 21;12(6). Epub 2020 Jun 21.

National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Carlos III Health Institute, 28029 Madrid, Spain.

Cholangiocarcinoma (CCA) and pancreatic adenocarcinoma (PDAC) may lead to the development of extrahepatic obstructive cholestasis. However, biliary stenoses can also be caused by benign conditions, and the identification of their etiology still remains a clinical challenge. We performed metabolomic and proteomic analyses of bile from patients with benign ( = 36) and malignant conditions, CCA ( = 36) or PDAC ( = 57), undergoing endoscopic retrograde cholangiopancreatography with the aim of characterizing bile composition in biliopancreatic disease and identifying biomarkers for the differential diagnosis of biliary strictures. Comprehensive analyses of lipids, bile acids and small molecules were carried out using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (H-NMR) in all patients. MS analysis of bile proteome was performed in five patients per group. We implemented artificial intelligence tools for the selection of biomarkers and algorithms with predictive capacity. Our machine-learning pipeline included the generation of synthetic data with properties of real data, the selection of potential biomarkers (metabolites or proteins) and their analysis with neural networks (NN). Selected biomarkers were then validated with real data. We identified panels of lipids ( = 10) and proteins ( = 5) that when analyzed with NN algorithms discriminated between patients with and without cancer with an unprecedented accuracy.
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http://dx.doi.org/10.3390/cancers12061644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352944PMC
June 2020

Epigenetic mechanisms and metabolic reprogramming in fibrogenesis: dual targeting of G9a and DNMT1 for the inhibition of liver fibrosis.

Gut 2021 02 23;70(2):388-400. Epub 2020 Apr 23.

CIBEREHD, Madrid, Spain

Objective: Hepatic stellate cells (HSC) transdifferentiation into myofibroblasts is central to fibrogenesis. Epigenetic mechanisms, including histone and DNA methylation, play a key role in this process. Concerted action between histone and DNA-mehyltransferases like G9a and DNMT1 is a common theme in gene expression regulation. We aimed to study the efficacy of CM272, a first-in-class dual and reversible G9a/DNMT1 inhibitor, in halting fibrogenesis.

Design: G9a and DNMT1 were analysed in cirrhotic human livers, mouse models of liver fibrosis and cultured mouse HSC. and expression was knocked down or inhibited with CM272 in human HSC (hHSC), and transcriptomic responses to transforming growth factor-β1 (TGFβ1) were examined. Glycolytic metabolism and mitochondrial function were analysed with Seahorse-XF technology. Gene expression regulation was analysed by chromatin immunoprecipitation and methylation-specific PCR. Antifibrogenic activity and safety of CM272 were studied in mouse chronic CCl administration and bile duct ligation (BDL), and in human precision-cut liver slices (PCLSs) in a new bioreactor technology.

Results: G9a and DNMT1 were detected in stromal cells in areas of active fibrosis in human and mouse livers. G9a and DNMT1 expression was induced during mouse HSC activation, and TGFβ1 triggered their chromatin recruitment in hHSC. G9a/DNMT1 knockdown and CM272 inhibited TGFβ1 fibrogenic responses in hHSC. TGFβ1-mediated profibrogenic metabolic reprogramming was abrogated by CM272, which restored gluconeogenic gene expression and mitochondrial function through on-target epigenetic effects. CM272 inhibited fibrogenesis in mice and PCLSs without toxicity.

Conclusions: Dual G9a/DNMT1 inhibition by compounds like CM272 may be a novel therapeutic strategy for treating liver fibrosis.
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http://dx.doi.org/10.1136/gutjnl-2019-320205DOI Listing
February 2021

Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis.

Nat Commun 2019 07 16;10(1):3126. Epub 2019 Jul 16.

UCL Institute for Liver and Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, WC1E 6BT, UK.

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.
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http://dx.doi.org/10.1038/s41467-019-11004-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635373PMC
July 2019

Chromatin dynamics during liver regeneration.

Semin Cell Dev Biol 2020 01 9;97:38-46. Epub 2019 Apr 9.

Hepatology Program, CIMA, University of Navarra, Pamplona, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, Pamplona, Spain. Electronic address:

Liver regeneration is the most important reaction of the liver to an injury. Indeed, the liver possesses an extraordinary regenerative capacity orchestrated by a highly coordinated response of all the different cell types in order to recover the tissue lost, while maintaining homeostasis and all the hepatic functions. To achieve this impressive physiological accomplishment, the liver experiences a transient but precisely controlled transcriptional reprogramming that allows the simultaneous activation and silencing of multiple genes at different stages of the regeneration process. Epigenetic events play a fundamental role in the organization of chromatin architecture and hence in the tight control of gene transcription. In this review, we will summarize the most relevant epigenetic modifications associated with the critical changes in gene expression and cellular behavior occurring during liver regeneration. We will discuss the relevance of DNA methylation, histone modifications, and chromatin remodelers, and the interplay between these epigenetic events, during the regeneration process, mainly after partial hepatectomy or after chemical injury.
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http://dx.doi.org/10.1016/j.semcdb.2019.03.004DOI Listing
January 2020

Splicing events in the control of genome integrity: role of SLU7 and truncated SRSF3 proteins.

Nucleic Acids Res 2019 04;47(7):3450-3466

Hepatology Program, CIMA, University of Navarra, Pamplona 31008, Spain.

Genome instability is related to disease development and carcinogenesis. DNA lesions are caused by genotoxic compounds but also by the dysregulation of fundamental processes like transcription, DNA replication and mitosis. Recent evidence indicates that impaired expression of RNA-binding proteins results in mitotic aberrations and the formation of transcription-associated RNA-DNA hybrids (R-loops), events strongly associated with DNA injury. We identify the splicing regulator SLU7 as a key mediator of genome stability. SLU7 knockdown results in R-loops formation, DNA damage, cell-cycle arrest and severe mitotic derangements with loss of sister chromatid cohesion (SCC). We define a molecular pathway through which SLU7 keeps in check the generation of truncated forms of the splicing factor SRSF3 (SRp20) (SRSF3-TR). Behaving as dominant negative, or by gain-of-function, SRSF3-TR impair the correct splicing and expression of the splicing regulator SRSF1 (ASF/SF2) and the crucial SCC protein sororin. This unique function of SLU7 was found in cancer cells of different tissue origin and also in the normal mouse liver, demonstrating a conserved and fundamental role of SLU7 in the preservation of genome integrity. Therefore, the dowregulation of SLU7 and the alterations of this pathway that we observe in the cirrhotic liver could be involved in the process of hepatocarcinogenesis.
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http://dx.doi.org/10.1093/nar/gkz014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468163PMC
April 2019

Targeting CCL2/CCR2 in Tumor-Infiltrating Macrophages: A Tool Emerging Out of the Box Against Hepatocellular Carcinoma.

Cell Mol Gastroenterol Hepatol 2019 4;7(2):293-294. Epub 2018 Dec 4.

Hepatology Program, Centro de Investigación Médica Aplicada, University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra-Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.jcmgh.2018.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354282PMC
March 2019

Splicing alterations contributing to cancer hallmarks in the liver: central role of dedifferentiation and genome instability.

Transl Gastroenterol Hepatol 2018 31;3:84. Epub 2018 Oct 31.

Hepatology Program, CIMA, University of Navarra, Pamplona, Spain.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. HCCs are molecularly heterogeneous tumors, and this complexity is to a great extent responsible for their poor response to conventional and targeted therapies. In this review we summarize recent evidence indicating that imbalanced expression of mRNA splicing factors can be a relevant source for this heterogeneity. We also discuss how these alterations may play a driver role in hepatocarcinogenesis by impinging on the general hallmarks of cancer. Considering the natural history of HCC, we focused on two pathogenic features that are characteristic of liver tumors: chromosomal instability and phenotypic de-differentiation. We highlight mechanisms connecting splicing derangement with these two processes and the enabling capacities acquired by liver cells along their neoplastic transformation. A thorough understanding of the alterations in the splicing machinery may also help to identify new HCC biomarkers and to design novel therapeutic strategies.
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http://dx.doi.org/10.21037/tgh.2018.10.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232053PMC
October 2018

The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis.

Hepatology 2019 04 4;69(4):1632-1647. Epub 2019 Mar 4.

Hepatology Program, University of Navarra, Cima, Pamplona, Spain.

Intrahepatic accumulation of bile acids (BAs) causes hepatocellular injury. Upon liver damage, a potent protective response is mounted to restore the organ's function. Epidermal growth factor receptor (EGFR) signaling is essential for regeneration after most types of liver damage, including cholestatic injury. However, EGFR can be activated by a family of growth factors induced during liver injury and regeneration. We evaluated the role of the EGFR ligand, amphiregulin (AREG), during cholestatic liver injury and regulation of AREG expression by BAs. First, we demonstrated increased AREG levels in livers from patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In two murine models of cholestatic liver injury, bile duct ligation (BDL) and alpha-naphthyl-isothiocyanate (ANIT) gavage, hepatic AREG expression was markedly up-regulated. Importantly, Areg mice showed aggravated liver injury after BDL and ANIT administration compared to Areg mice. Recombinant AREG protected from ANIT and BDL-induced liver injury and reduced BA-triggered apoptosis in liver cells. Oral BA administration induced ileal and hepatic Areg expression, and, interestingly, cholestyramine feeding reduced postprandial Areg up-regulation in both tissues. Most interestingly, Areg mice displayed high hepatic cholesterol 7 α-hydroxylase (CYP7A1) expression, reduced serum cholesterol, and high BA levels. Postprandial repression of Cyp7a1 was impaired in Areg mice, and recombinant AREG down-regulated Cyp7a1 mRNA in hepatocytes. On the other hand, BAs promoted AREG gene expression and protein shedding in hepatocytes. This effect was mediated through the farnesoid X receptor (FXR), as demonstrated in Fxr mice, and involved EGFR transactivation. Finally, we show that hepatic EGFR expression is indirectly induced by BA-FXR through activation of suppressor of cytokine signaling-3 (SOC3). Conclusion: AREG-EGFR signaling protects from cholestatic injury and participates in the physiological regulation of BA synthesis.
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http://dx.doi.org/10.1002/hep.30348DOI Listing
April 2019

MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis.

Cell Death Dis 2018 09 20;9(10):958. Epub 2018 Sep 20.

CIC bioGUNE, Centro de Investigación Cooperativa en Biociencias, Derio, Bizkaia, Spain.

Glycine N-methyltransferase (GNMT) is the most abundant methyltransferase in the liver and a master regulator of the transmethylation flux. GNMT downregulation leads to loss of liver function progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Moreover, GNMT deficiency aggravates cholestasis-induced fibrogenesis. To date, little is known about the mechanisms underlying downregulation of GNMT levels in hepatic fibrosis and cirrhosis. On this basis, microRNAs are epigenetic regulatory elements that play important roles in liver pathology. In this work, we aim to study the regulation of GNMT by microRNAs during liver fibrosis and cirrhosis. Luciferase assay on the 3'UTR-Gnmt was used to confirm in silico analysis showing that GNMT is potentially targeted by the microRNA miR-873-5p. Correlation between GNMT and miR-873-5p in human cholestasis and cirrhosis together with miR-873-5p inhibition in vivo in different mouse models of liver cholestasis and fibrosis [bile duct ligation and Mdr2 (Abcb4) mouse] were then assessed. The analysis of liver tissue from cirrhotic and cholestatic patients, as well as from the animal models, showed that miR-873-5p inversely correlated with the expression of GNMT. Importantly, high circulating miR-873-5p was also detected in cholestastic and cirrhotic patients. Preclinical studies with anti-miR-873-5p treatment in bile duct ligation and Mdr2 mice recovered GNMT levels in association with ameliorated inflammation and fibrosis mainly by counteracting hepatocyte apoptosis and cholangiocyte proliferation. In conclusion, miR-873-5p emerges as a novel marker for liver fibrosis, cholestasis, and cirrhosis and therapeutic approaches based on anti-miR-873-5p may be effective treatments for liver fibrosis and cholestatic liver disease.
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http://dx.doi.org/10.1038/s41419-018-1014-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148053PMC
September 2018

Fibroblast growth factors 19 and 21 in acute liver damage.

Ann Transl Med 2018 Jun;6(12):257

Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.

Currently there are very few pharmacological options available to treat acute liver injury. Because its natural exposure to noxious stimuli the liver has developed a strong endogenous hepatoprotective capacity. Indeed, experimental evidence exposed a variety of endogenous hepatic and systemic responses naturally activated to protect the hepatic parenchyma and to foster liver regeneration, therefore preserving individual's survival. The fibroblast growth factor (FGF) family encompasses a range of polypeptides with important effects on cellular differentiation, growth survival and metabolic regulation in adult organisms. Among these FGFs, FGF19 and FGF21 are endocrine hormones that profoundly influence systemic metabolism but also exert important hepatoprotective activities. In this review, we revisit the biology of these factors and highlight their potential application for the clinical management of acute liver injury.
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http://dx.doi.org/10.21037/atm.2018.05.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046301PMC
June 2018

Dual Targeting of Histone Methyltransferase G9a and DNA-Methyltransferase 1 for the Treatment of Experimental Hepatocellular Carcinoma.

Hepatology 2019 02 4;69(2):587-603. Epub 2019 Jan 4.

Hepatology Program, Cima-University of Navarra, Pamplona, Spain.

Epigenetic modifications such as DNA and histone methylation functionally cooperate in fostering tumor growth, including that of hepatocellular carcinoma (HCC). Pharmacological targeting of these mechanisms may open new therapeutic avenues. We aimed to determine the therapeutic efficacy and potential mechanism of action of our dual G9a histone-methyltransferase and DNA-methyltransferase 1 (DNMT1) inhibitor in human HCC cells and their crosstalk with fibrogenic cells. The expression of G9a and DNMT1, along with that of their molecular adaptor ubiquitin-like with PHD and RING finger domains-1 (UHRF1), was measured in human HCCs (n = 268), peritumoral tissues (n = 154), and HCC cell lines (n = 32). We evaluated the effect of individual and combined inhibition of G9a and DNMT1 on HCC cell growth by pharmacological and genetic approaches. The activity of our lead compound, CM-272, was examined in HCC cells under normoxia and hypoxia, human hepatic stellate cells and LX2 cells, and xenograft tumors formed by HCC or combined HCC+LX2 cells. We found a significant and correlative overexpression of G9a, DNMT1, and UHRF1 in HCCs in association with poor prognosis. Independent G9a and DNMT1 pharmacological targeting synergistically inhibited HCC cell growth. CM-272 potently reduced HCC and LX2 cells proliferation and quelled tumor growth, particularly in HCC+LX2 xenografts. Mechanistically, CM-272 inhibited the metabolic adaptation of HCC cells to hypoxia and induced a differentiated phenotype in HCC and fibrogenic cells. The expression of the metabolic tumor suppressor gene fructose-1,6-bisphosphatase (FBP1), epigenetically repressed in HCC, was restored by CM-272. Conclusion: Combined targeting of G9a/DNMT1 with compounds such as CM-272 is a promising strategy for HCC treatment. Our findings also underscore the potential of differentiation therapy in HCC.
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http://dx.doi.org/10.1002/hep.30168DOI Listing
February 2019

LKB1: Controlling Quiescence and Genomic Integrity at Home.

Trends Endocrinol Metab 2018 10 5;29(10):668-670. Epub 2018 Apr 5.

Hepatology Program, Cima-University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigaciones Sanitarias de Navarra (IDISNA), Pamplona, Spain.

The pleiotropic liver kinase B1 (LKB1) controls metabolism, cell polarity, and proliferation in an apparently cell- and context-specific manner. A recent study in Cell Reports has demonstrated that LKB1 is essential to maintain the characteristic quiescence of the liver and to secure genomic integrity during liver regeneration independently of AMPK.
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http://dx.doi.org/10.1016/j.tem.2018.03.017DOI Listing
October 2018

Engineered fibroblast growth factor 19 protects from acetaminophen-induced liver injury and stimulates aged liver regeneration in mice.

Cell Death Dis 2017 10 5;8(10):e3083. Epub 2017 Oct 5.

CIBERehd, Instituto de Salud Carlos III, Clinica Universidad de Navarra, Avda, Pio XII, n 36, Pamplona 31008, Spain.

The liver displays a remarkable regenerative capacity triggered upon tissue injury or resection. However, liver regeneration can be overwhelmed by excessive parenchymal destruction or diminished by pre-existing conditions hampering repair. Fibroblast growth factor 19 (FGF19, rodent FGF15) is an enterokine that regulates liver bile acid and lipid metabolism, and stimulates hepatocellular protein synthesis and proliferation. FGF19/15 is also important for liver regeneration after partial hepatectomy (PH). Therefore recombinant FGF19 would be an ideal molecule to stimulate liver regeneration, but its applicability may be curtailed by its short half-life. We developed a chimaeric molecule termed Fibapo in which FGF19 is covalently coupled to apolipoprotein A-I. Fibapo retains FGF19 biological activities but has significantly increased half-life and hepatotropism. Here we evaluated the pro-regenerative activity of Fibapo in two clinically relevant models where liver regeneration may be impaired: acetaminophen (APAP) poisoning, and PH in aged mice. The only approved therapy for APAP intoxication is N-acetylcysteine (NAC) and no drugs are available to stimulate liver regeneration. We demonstrate that Fibapo reduced liver injury and boosted regeneration in APAP-intoxicated mice. Fibapo improved survival of APAP-poisoned mice when given at later time points, when NAC is ineffective. Mechanistically, Fibapo accelerated recovery of hepatic glutathione levels, potentiated cell growth-related pathways and increased functional liver mass. When Fibapo was administered to old mice prior to PH, liver regeneration was markedly increased. The exacerbated injury developing in these mice upon PH was attenuated, and the hepatic biosynthetic capacity was enhanced. Fibapo reversed metabolic and molecular alterations that impede regeneration in aged livers. It reduced liver steatosis and downregulated p21 and hepatocyte nuclear factor 4 α (Hnf4α) levels, whereas it stimulated Foxm1b gene expression. Together our findings indicate that FGF19 variants retaining the metabolic and growth-promoting effects of this enterokine may be valuable for the stimulation of liver regeneration.
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http://dx.doi.org/10.1038/cddis.2017.480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682649PMC
October 2017

Bile acids, FGF15/19 and liver regeneration: From mechanisms to clinical applications.

Biochim Biophys Acta Mol Basis Dis 2018 04 12;1864(4 Pt B):1326-1334. Epub 2017 Jul 12.

CIBERehd, Instituto de Salud Carlos III, Clinica Universidad de Navarra, Avda. Pio XII, n 36, 31008 Pamplona, Spain; Hepatology Programme, CIMA, Idisna, Universidad de Navarra, Avda, Pio XII, n 55, 31008 Pamplona, Spain. Electronic address:

The liver has an extraordinary regenerative capacity rapidly triggered upon injury or resection. This response is intrinsically adjusted in its initiation and termination, a property termed the "hepatostat". Several molecules have been involved in liver regeneration, and among them bile acids may play a central role. Intrahepatic levels of bile acids rapidly increase after resection. Through the activation of farnesoid X receptor (FXR), bile acids regulate their hepatic metabolism and also promote hepatocellular proliferation. FXR is also expressed in enterocytes, where bile acids stimulate the expression of fibroblast growth factor 15/19 (FGF15/19), which is released to the portal blood. Through the activation of FGFR4 on hepatocytes FGF15/19 regulates bile acids synthesis and finely tunes liver regeneration as part of the "hepatostat". Here we review the experimental evidences supporting the relevance of the FXR-FGF15/19-FGFR4 axis in liver regeneration and discuss potential therapeutic applications of FGF15/19 in the prevention of liver failure. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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http://dx.doi.org/10.1016/j.bbadis.2017.06.025DOI Listing
April 2018

Fibroblast Growth Factor 15/19 in Hepatocarcinogenesis.

Dig Dis 2017 1;35(3):158-165. Epub 2017 Mar 1.

CIBERehd, University Clinic Navarra, Instituto de Salud Carlos III, Pamplona, Spain.

Background: Advanced hepatocellular carcinoma (HCC) is a neoplastic disease with a very bad prognosis and increasing worldwide incidence. HCCs are resistant to conventional chemotherapy and the multikinase inhibitor sorafenib is the only agent that has shown some clinical efficacy. It is therefore important to identify key molecular mechanisms driving hepatocarcinogenesis for the development of more efficacious therapies. However, HCCs are heterogeneous tumors and different molecular subclasses have been characterized. This heterogeneity may underlie the poor performance of most of the targeted therapies so far tested in HCC patients. The fibroblast growth factor 15/19 (FGF15/19), FGF receptor 4 (FGFR4) and beta-Klotho (KLB) correceptor signaling system, a key regulator of bile acids (BA) synthesis and intermediary metabolism, is emerging as an important player in hepatocarcinogenesis. Key Messages: Aberrant signaling through the FGF15/19-FGFR4 pathway participates in the neoplastic behavior of HCC cells, promotes HCC development in mice and its overexpression has been characterized in a subset of HCC tumors from patients with poorer prognosis. Pharmacological interference with FGF15/19-FGFR4 signaling inhibits experimental hepatocarcinogenesis, and specific FGFR4 inhibitors are currently being tested in selected HCC patients with tumoral FGF19-FGFR4/KLB expression.

Conclusions: Interference with FGF19-FGFR4 signaling represents a novel strategy in HCC therapy. Selection of candidate patients based on tumoral FGF19-FGFR4/KLB levels as biomarkers may result in increased efficacy of FGFR4-targeted drugs. Nevertheless, attention should be paid to the potential on target toxic effects of FGFR4 inhibitors due to the key role of this signaling system in BA metabolism.
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http://dx.doi.org/10.1159/000450905DOI Listing
May 2017

Fibroblast growth factor 15/19 (FGF15/19) protects from diet-induced hepatic steatosis: development of an FGF19-based chimeric molecule to promote fatty liver regeneration.

Gut 2017 10 24;66(10):1818-1828. Epub 2017 Jan 24.

Hepatology Programme, CIMA-University of Navarra, IdiSNA, CIBEREHD, Pamplona, Spain.

Objective: Fibroblast growth factor 15/19 (FGF15/19), an enterokine that regulates synthesis of hepatic bile acids (BA), has been proposed to influence fat metabolism. Without FGF15/19, mouse liver regeneration after partial hepatectomy (PH) is severely impaired. We studied the role of FGF15/19 in response to a high fat diet (HFD) and its regulation by saturated fatty acids. We developed a fusion molecule encompassing FGF19 and apolipoprotein A-I, termed Fibapo, and evaluated its pharmacological properties in fatty liver regeneration.

Design: mice were fed a HFD. Liver fat and the expression of fat metabolism and endoplasmic reticulum (ER) stress-related genes were measured. Influence of palmitic acid (PA) on expression was determined in mice and in human liver cell lines. In vivo half-life and biological activity of Fibapo and FGF19 were compared. Hepatoprotective and proregenerative activities of Fibapo were evaluated in obese mice undergoing PH.

Results: Hepatosteatosis and ER stress were exacerbated in HFD-fed mice. Hepatic expression of was elevated in mice, being reversed by FGF19 treatment. PA induced expression in mouse ileum and human liver cells, and FGF19 protected from PA-mediated ER stress and cytotoxicity. Fibapo reduced liver BA and lipid accumulation, inhibited ER stress and showed enhanced half-life. Fibapo provided increased mice survival and improved regeneration upon PH.

Conclusions: FGF15/19 is essential for hepatic metabolic adaptation to dietary fat being a physiological regulator of expression Perioperative administration of Fibapo improves fatty liver regeneration.
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http://dx.doi.org/10.1136/gutjnl-2016-312975DOI Listing
October 2017
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