RESUMEN
BACKGROUND & AIMS: Owing to the lack of genetic animal models that adequately recreate key clinical characteristics of cirrhosis, the molecular pathogenesis of cirrhosis has been poorly characterized, and treatments remain limited. Hence, we aimed to better elucidate the pathological mechanisms of cirrhosis using a novel murine model. METHODS: We report on the first murine genetic model mimicking human cirrhosis induced by hepatocyte-specific elimination of microspherule protein 1 (MCRS1), a member of non-specific lethal (NSL) and INO80 chromatin-modifier complexes. Using this genetic tool with other mouse models, cell culture and human samples, combined with quantitative proteomics, single nuclei/cell RNA sequencing and chromatin immunoprecipitation assays, we investigated mechanisms of cirrhosis. RESULTS: MCRS1 loss in mouse hepatocytes modulates the expression of bile acid (BA) transporters - with a pronounced downregulation of Na+-taurocholate cotransporting polypeptide (NTCP) - concentrating BAs in sinusoids and thereby activating hepatic stellate cells (HSCs) via the farnesoid X receptor (FXR), which is predominantly expressed in human and mouse HSCs. Consistently, re-expression of NTCP in mice reduces cirrhosis, and genetic ablation of FXR in HSCs suppresses fibrotic marks in mice and in vitro cell culture. Mechanistically, deletion of a putative SANT domain from MCRS1 evicts histone deacetylase 1 from its histone H3 anchoring sites, increasing histone acetylation of BA transporter genes, modulating their expression and perturbing BA flow. Accordingly, human cirrhosis displays decreased nuclear MCRS1 and NTCP expression. CONCLUSIONS: Our data reveal a previously unrecognized function of MCRS1 as a critical histone acetylation regulator, maintaining gene expression and liver homeostasis. MCRS1 loss induces acetylation of BA transporter genes, perturbation of BA flow, and consequently, FXR activation in HSCs. This axis represents a central and universal signaling event in cirrhosis, which has significant implications for cirrhosis treatment. LAY SUMMARY: By genetic ablation of MCRS1 in mouse hepatocytes, we generate the first genetic mouse model of cirrhosis that recapitulates human features. Herein, we demonstrate that the activation of the bile acid/FXR axis in liver fibroblasts is key in cirrhosis development.
Asunto(s)
Histonas , Proteínas de Unión al ARN , Receptores Citoplasmáticos y Nucleares , Acetilación , Animales , Ácidos y Sales Biliares/metabolismo , Proteínas Portadoras , Histonas/metabolismo , Hígado/patología , Cirrosis Hepática/patología , Glicoproteínas de Membrana , Ratones , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismoAsunto(s)
Atetosis/genética , Corea/genética , Hipotiroidismo Congénito/genética , Mutación/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Factor Nuclear Tiroideo 1/genética , Adulto , Anciano , Secuencia de Aminoácidos , Línea Celular Tumoral , Niño , Femenino , Células HeLa , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Colorectal cancer is an important public health problem in Spain. Over the last decade, several regions have carried out screening programmes, but population participation rates remain below recommended European goals. Reminders on electronic medical records have been identified as a low-cost and high-reach strategy to increase participation. Further knowledge is needed about their effect in a population-based screening programme. The main aim of this study is to evaluate the effectiveness of an electronic reminder to promote the participation in a population-based colorectal cancer screening programme. Secondary aims are to learn population's reasons for refusing to take part in the screening programme and to find out the health professionals' opinion about the official programme implementation and on the new computerised tool. METHODS/DESIGN: This is a parallel randomised trial with a cross-sectional second stage. PARTICIPANTS: all the invited subjects to participate in the public colorectal cancer screening programme that includes men and women aged between 50-69, allocated to the eleven primary care centres of the study and all their health professionals. The randomisation unit will be the primary care physician. The intervention will consist of activating an electronic reminder, in the patient's electronic medical record, in order to promote colorectal cancer screening, during a synchronous medical appointment, throughout the year that the intervention takes place. A comparison of the screening rates will then take place, using the faecal occult blood test of the patients from the control and the intervention groups. We will also take a questionnaire to know the opinions of the health professionals. The main outcome is the screening status at the end of the study. Data will be analysed with an intention-to-treat approach. DISCUSSION: We expect that the introduction of specific reminders in electronic medical records, as a tool to facilitate and encourage direct referral by physicians and nurse practitioners to perform colorectal cancer screening will mean an increase in participation of the target population. The introduction of this new software tool will have good acceptance and increase compliance with recommendations from health professionals. TRIAL REGISTRATION: Clinical Trials.gov identifier NCT01877018.
