Histone acetylation of bile acid transporter genes plays a critical role in cirrhosis.

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.

Is liver regeneration key in hepatocellular carcinoma development?

The liver is the largest organ of the mammalian body and has the remarkable ability to fully regenerate in order to maintain tissue homeostasis. The adult liver consists of hexagonal lobules, each with a central vein surrounded by six portal triads localized in the lobule border containing distinct parenchymal and nonparenchymal cells. Because the liver is continuously exposed to diverse stress signals, several sophisticated regenerative processes exist to restore its functional status following impairment. However, these stress signals can affect the liver's capacity to regenerate and may lead to the development of hepatocellular carcinoma (HCC), one of the most aggressive liver cancers. Here, we review the mechanisms of hepatic regeneration and their potential to influence HCC development.

Impacto en la actividad asistencial y la salud de los profesionales de Atención Primaria durante el confinamiento / Impact on healthcare activities and the health of Primary Care professionals during lockdown

Objetivo: conocer el impacto del confinamiento en los hábitos de vida, la salud física y emocional de los trabajadores de Atención Primaria.Método: estudio transversal. Encuesta online a trabajadores que desempeñaron su actividad en dos centros de salud de Vizcaya, uno con atención presencial a pacientes con patología compatible con COVID-19 y otro que desarrolló actividad telefónica con pacientes con otras patologías. Se realizó un análisis descriptivo. Se compararon las variables categóricas mediante Chi cuadrado o test exacto de Fisher.Resultados: participaron 70 (54,29%) profesionales de 138, mayoritariamente enfermeras y médicos (71% en centro de salud con atención presencial y 72% en centro de salud con atención telefónica). No se encontraron diferencias en cuanto a la práctica de ejercicio físico ni alimentación, excepto en el consumo de comida precocinada casi todos los días (83,67% en centro con atención telefónica frente al 9,52% en centro con atención presencial, p< 0,001). Los sujetos de estudio han percibido un empeoramiento durante el confinamiento en relación al tiempo de actividad física (p= 0,027), alimentación (p< 0,001), tiempo delante de las pantallas (p= 0,010), salud física (p= 0,007) y bienestar emocional. Sin embargo, se ha percibido una mejoría en ambos grupos en relación a la tolerancia a la frustración (p< 0,001). El grupo con actividad presencial ha tenido un mayor impacto negativo en sus hábitos durante el confinamiento.Conclusiones: el confinamiento tuvo un cierto impacto en los hábitos de vida, la salud física y emocional de los trabajadores de Atención Primaria, y fue más acusado en el centro en el que desempeñaron su actividad laboral de forma presencial.(AU)

Objective: to understand the impact of lockdown on the lifestyle and physical and emotional health of Primary Care workers.Method: a cross-sectional study: an online survey for workers who performed their activity in two health centres in Bilbao, one with face-to-face assistance for patients with conditions compatible with COVID-19, and the other one conducting activity by telephone with patients presenting other conditions. A descriptive analysis was conducted; categorical variables were compared through Chi Square or Fisher’s Exact Test.Results: seventy (70 – 54.29%) professionals participated, out of 138; the majority were nurses and doctors (71% in the health centre with face-to-face care and 72% in the health centre with telephone care). No differences were found regarding physical exercise or diet, except in the fact of eating ready-made food almost every day (83.67% in the centre with care by telephone vs. 9.52% in the centre with face-to-face care, p< 0,001). The subjects of the study have perceived worsening during lockdown regarding their time of physical activity (p= 0.027), diet (p< 0.001), time spent in front of screens (p= 0.010), physical health (p= 0.007) and emotional wellbeing. However, an improvement was perceived in both arms regarding tolerance to frustration (p< 0.001). The arm with face-to-face activity has experienced a greater negative impact on their lifestyle during lockdown.Conclusions: lockdown has had some impact on the lifestyle and physical and emotional health of Primary Care workers, and this has been more pronounced in the centre where they performed their work activity face-to-face.(AU)