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Under chronic stress, cells must balance competing demands between cellular survival and tissue function. In metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD/NASH), hepatocytes cooperate with structural and immune cells to perform crucial metabolic, synthetic, and detoxification functions despite nutrient imbalances. While prior work has emphasized stress-induced drivers of cell death, the dynamic adaptations of surviving cells and their functional repercussions remain unclear. Namely, we do not know which pathways and programs define cellular responses, what regulatory factors mediate (mal)adaptations, and how this aberrant activity connects to tissue-scale dysfunction and long-term disease outcomes. Here, by applying longitudinal single-cell multi -omics to a mouse model of chronic metabolic stress and extending to human cohorts, we show that stress drives survival-linked tradeoffs and metabolic rewiring, manifesting as shifts towards development-associated states in non-transformed hepatocytes with accompanying decreases in their professional functionality. Diet-induced adaptations occur significantly prior to tumorigenesis but parallel tumorigenesis-induced phenotypes and predict worsened human cancer survival. Through the development of a multi -omic computational gene regulatory inference framework and human in vitro and mouse in vivo genetic perturbations, we validate transcriptional (RELB, SOX4) and metabolic (HMGCS2) mediators that co-regulate and couple the balance between developmental state and hepatocyte functional identity programming. Our work defines cellular features of liver adaptation to chronic stress as well as their links to long-term disease outcomes and cancer hallmarks, unifying diverse axes of cellular dysfunction around core causal mechanisms.
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BACKGROUND: Therapies to prevent alcohol-associated liver disease (ALD) in high-risk patients are needed. AIMS: In this retrospective association study, we examined whether patients with alcohol use disorder (AUD) who reported greater exercise were less likely to develop liver disease. METHODS: In this retrospective cohort study, we used the Mass General Brigham Biobank to investigate the impact of both moderate-high and light-intensity exercise on the development of ALD in patients with AUD, using clinician-provided diagnostic International Classification of Diseases 10 codes. Exercise was evaluated using a questionnaire completed after an AUD diagnosis, and before evidence of liver disease. Cox regressions were used to generate hazard ratios (HRs) for the development of ALD. RESULTS: 1987 patients met inclusion criteria. These patients were followed for an average of 10.7 years. In multivariable analyses, we found that patients that reported at least 2.5 h of moderate-high intensity exercise/week (confidence interval recommendation for exercise) were less likely to develop ALD compared to patients that did not exercise (HR: 0.26, 95%CI: 0.085-0.64, P = 0.007). Indeed, each hour of moderate-high intensity exercise was associated with progressively decreasing odds of developing ALD (HR: 0.76, 95%CI: 0.58-0.91, P = 0.02). Conversely, patients who did not engage in any moderate-high intensity exercise were more likely to develop ALD (HR: 2.76, 95%CI: 1.44-5.40, P = 0.003). CONCLUSIONS: In our cohort, patients with AUD who reported moderate-high intensity exercise showed a lower association with incidence of ALD development than patients who did not exercise.
Asunto(s)
Alcoholismo , Hepatopatías Alcohólicas , Trasplante de Hígado , Humanos , Estudios Retrospectivos , Hepatopatías Alcohólicas/complicaciones , Consumo de Bebidas Alcohólicas/efectos adversos , Alcoholismo/epidemiología , Alcoholismo/complicacionesRESUMEN
Obesity exerts both direct and indirect effects on gastrointestinal function. From physical effects of central adiposity on intragastric pressure resulting in higher incidence of reflux to dyslipidemia and effects on gallstone disease, the gastrointestinal manifestations of obesity are wide-ranging. Of particular emphasis is the identification and management of non-alcoholic fatty liver disease including non-invasive assessment and lifestyle and pharmacologic interventions for patients with non-alcoholic steatohepatitis. Additional focus is on the impact of obesity and western diet on intestinal disorders and colorectal cancer. Bariatric interventions involving the gastrointestinal tract are also discussed.
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Reflujo Gastroesofágico , Enfermedades Gastrointestinales , Enfermedad del Hígado Graso no Alcohólico , Humanos , Obesidad/complicaciones , Obesidad/epidemiología , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/terapia , Enfermedades Gastrointestinales/etiología , Enfermedades Gastrointestinales/terapiaRESUMEN
Environmental enteropathy (EE) is a subclinical condition of the small intestine that is highly prevalent in low- and middle-income countries. It is thought to be a key contributing factor to childhood malnutrition, growth stunting, and diminished oral vaccine responses. Although EE has been shown to be the by-product of a recurrent enteric infection, its full pathophysiology remains unclear. Here, we mapped the cellular and molecular correlates of EE by performing high-throughput, single-cell RNA-sequencing on 33 small intestinal biopsies from 11 adults with EE in Lusaka, Zambia (eight HIV-negative and three HIV-positive), six adults without EE in Boston, United States, and two adults in Durban, South Africa, which we complemented with published data from three additional individuals from the same clinical site. We analyzed previously defined bulk-transcriptomic signatures of reduced villus height and decreased microbial translocation in EE and showed that these signatures may be driven by an increased abundance of surface mucosal cells-a gastric-like subset previously implicated in epithelial repair in the gastrointestinal tract. In addition, we determined cell subsets whose fractional abundances associate with EE severity, small intestinal region, and HIV infection. Furthermore, by comparing duodenal EE samples with those from three control cohorts, we identified dysregulated WNT and MAPK signaling in the EE epithelium and increased proinflammatory cytokine gene expression in a T cell subset highly expressing a transcriptional signature of tissue-resident memory cells in the EE cohort. Together, our work elucidates epithelial and immune correlates of EE and nominates cellular and molecular targets for intervention.
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Infecciones por VIH , Enfermedades Intestinales , Adulto , Niño , Infecciones por VIH/patología , Humanos , Enfermedades Intestinales/metabolismo , Enfermedades Intestinales/patología , Mucosa Intestinal/metabolismo , Sudáfrica , ZambiaRESUMEN
Importance: Alcohol-associated liver disease (ALD) is one of the most devastating complications of alcohol use disorder (AUD), an increasingly prevalent condition. Medical addiction therapy for AUD may play a role in protecting against the development and progression of ALD. Objective: To ascertain whether medical addiction therapy was associated with an altered risk of developing ALD in patients with AUD. Design, Setting, and Participants: This retrospective cohort study used the Mass General Brigham Biobank, an ongoing research initiative that had recruited 127â¯480 patients between its start in 2010 and August 17, 2021, when data for the present study were retrieved. The mean follow-up duration from AUD diagnosis was 9.2 years. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis codes were used to identify ALD and AUD diagnoses. Exposures: Medical addiction therapy was defined as the documented use of disulfiram, acamprosate, naltrexone, gabapentin, topiramate, or baclofen. Patients were considered to be treated if they initiated medical addiction therapy before the relevant outcome. Main Outcomes and Measures: Adjusted odds ratios (aORs) for the development of ALD and hepatic decompensation were calculated and adjusted for multiple risk factors. Results: The cohort comprised 9635 patients with AUD, of whom 5821 were male individuals (60.4%), and the mean (SD) age was 54.8 (16.5) years. A total of 1135 patients (11.8%) had ALD and 3906 patients (40.5%) were treated with medical addiction therapy. In multivariable analyses, medical addiction therapy for AUD was associated with decreased incidence of ALD (aOR, 0.37; 95% CI, 0.31-0.43; P < .001). This association was evident for naltrexone (aOR, 0.67; 95% CI, 0.46-0.95; P = .03), gabapentin (aOR, 0.36; 95% CI, 0.30-0.43; P < .001), topiramate (aOR, 0.47; 95% CI, 0.32-0.66; P < .001), and baclofen (aOR, 0.57; 95% CI, 0.36-0.88; P = .01). In addition, pharmacotherapy for AUD was associated with lower incidence of hepatic decompensation in patients with cirrhosis (aOR, 0.35; 95% CI, 0.23-0.53, P < .001), including naltrexone (aOR, 0.27; 95% CI, 0.10-0.64; P = .005) and gabapentin (aOR, 0.36; 95% CI, 0.23-0.56; P < .001). This association persisted even when medical addiction therapy was initiated only after the diagnosis of cirrhosis (aOR, 0.41; 95% CI, 0.23-0.71; P = .002). Conclusions and Relevance: Results of this study showed that receipt of medical addiction therapy for AUD was associated with reduced incidence and progression of ALD. The associations of individual pharmacotherapy with the outcomes of ALD and hepatic decompensation varied widely.
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Alcoholismo , Alcoholismo/complicaciones , Alcoholismo/epidemiología , Baclofeno/uso terapéutico , Femenino , Gabapentina , Humanos , Incidencia , Cirrosis Hepática , Masculino , Persona de Mediana Edad , Naltrexona/uso terapéutico , Estudios Retrospectivos , Topiramato/uso terapéuticoRESUMEN
BACKGROUND: Cerebrospinal fluid ascites is a rare complication of ventriculoperitoneal shunting and is the result of infection and subsequent peritonitis in the majority of cases. Sterile cerebrospinal fluid ascites in which no known infectious etiology is identified, is even more unusual. CASE PRESENTATION: A 26-year-old female with Loeys-Dietz syndrome and congenital hydrocephalus treated with a ventriculoperitoneal shunt, was evaluated after developing new-onset ascites of unclear etiology after abdominal surgery for repair of an aortic aneurysm requiring multiple therapeutic paracenteses. Her serum ascites albumin gradient (SAAG) was greater than 1.1, suggestive of a portal hypertensive etiology. Gram stain as well as multiple cultures of her ascites fluid were both negative. Extensive investigation including hepatic venous portal gradient measurement and liver biopsy revealed no evidence of hepatic disease or portal hypertension. She was ultimately found to have sterile cerebrospinal fluid ascites which was treated successfully with a peritoneovenous shunt. CONCLUSION: Sterile cerebrospinal fluid ascites is a rare clinical entity that has only been reported approximately 50 times in the medical literature. In this report, we also highlight it as a rare cause of high SAAG ascites. Moreover, we describe the use of a peritoneovenous shunt as a novel therapeutic option in the management of this condition.
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Ascitis/etiología , Derivación Ventriculoperitoneal/efectos adversos , Adulto , Ascitis/diagnóstico , Ascitis/terapia , Líquido Ascítico/metabolismo , Femenino , Humanos , Hidrocefalia/terapia , Síndrome de Loeys-Dietz , Derivación Peritoneovenosa , Albúmina Sérica/metabolismoRESUMEN
OBJECTIVES: Each year in the United States, approximately 40000 patients with a liver disorder will progress to end-stage liver disease and about 30000 of those patients will subsequently die from this condition. Liver transplant remains the definitive treatment option for end-stage liver disease, and understanding the causes of posttransplant mortality is an ongoing area of investigation. MATERIALS AND METHODS: In this retrospective cohort study, patients who underwent orthotopic liver transplant between January 2012 and January 2015 at the Johns Hopkins Hospital Liver Transplant Program were reviewed by a single reviewer for cardiac events in the 30 days after transplant or during the index admission. RESULTS: Of the 145 patients included, 30 (20.6%) were identified as having experienced a cardiac event during the defined postoperative period. Overall 1-year mortality for the cohort of 145 patients was 11.7%; however, 1-year mortality in those who had a cardiac event was 36.7% compared with 5.2% in the noncardiac event group (odds ratio = 18.17; P < .001). Although there was a statistically significant difference in age between the groups (58.6 vs 52.3 years old), once accounted for in multivariate analysis, a posttransplant cardiac event was still a statistically significant variable in 1-year mortality (odds ratio = 89.16; 95% confidence interval, 2.71-2933.95; P = .012). Similarly, hepatocellular carcinoma, sex, age, and presence of diabetes had little effect on 1-year mortality when we compared those patients who experienced a cardiac event in the first 30 days versus those who did not (odds ratio = 100.82; 95% confidence interval, 2.15-4726.12; P = .019). CONCLUSIONS: Recipients who experience cardiac events within 30 days after transplant have increased 1-year posttransplant mortality. This highlights the importance of cardiac risk stratification before transplant.
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Enfermedad Hepática en Estado Terminal/cirugía , Cardiopatías/mortalidad , Trasplante de Hígado , Complicaciones Posoperatorias/mortalidad , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de TiempoRESUMEN
Colonic tissues in Inflammatory Bowel Disease (IBD) patients exhibit oxygen deprivation and activation of hypoxia-inducible factor 1α and 2α (HIF-1α and HIF-2α), which mediate cellular adaptation to hypoxic stress. Notably, macrophages and neutrophils accumulate preferentially in hypoxic regions of the inflamed colon, suggesting that myeloid cell functions in colitis are HIF-dependent. By depleting ARNT (the obligate heterodimeric binding partner for both HIFα subunits) in a murine model, we demonstrate here that myeloid HIF signaling promotes the resolution of acute colitis. Specifically, myeloid pan-HIF deficiency exacerbates infiltration of pro-inflammatory neutrophils and Ly6C+ monocytic cells into diseased tissue. Myeloid HIF ablation also hinders macrophage functional conversion to a protective, pro-resolving phenotype, and elevates gut serum amyloid A levels during the resolution phase of colitis. Therefore, myeloid cell HIF signaling is required for efficient resolution of inflammatory damage in colitis, implicating serum amyloid A in this process.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Hipoxia de la Célula/fisiología , Colitis/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Macrófagos/inmunología , Neutrófilos/inmunología , Proteína Amiloide A Sérica/análisis , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas Portadoras/genética , Colitis/inducido químicamente , Colon/citología , Colon/inmunología , Colon/patología , Modelos Animales de Enfermedad , Proteínas Fetales/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Leucocitos Mononucleares/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/genéticaRESUMEN
Hypoxia-inducible factors (HIFs) accumulate in both neoplastic and inflammatory cells within the tumor microenvironment and impact the progression of a variety of diseases, including colorectal cancer. Pharmacological HIF inhibition represents a novel therapeutic strategy for cancer treatment. We show here that acriflavine (ACF), a naturally occurring compound known to repress HIF transcriptional activity, halts the progression of an autochthonous model of established colitis-associated colon cancer (CAC) in immunocompetent mice. ACF treatment resulted in decreased tumor number, size and advancement (based on histopathological scoring) of CAC. Moreover, ACF treatment corresponded with decreased macrophage infiltration and vascularity in colorectal tumors. Importantly, ACF treatment inhibited the hypoxic induction of M-CSFR, as well as the expression of the angiogenic factor (vascular endothelial growth factor), a canonical HIF target, with little to no impact on the Nuclear factor-kappa B pathway in bone marrow-derived macrophages. These effects probably explain the observed in vivo phenotypes. Finally, an allograft tumor model further confirmed that ACF treatment inhibits tumor growth through HIF-dependent mechanisms. These results suggest pharmacological HIF inhibition in multiple cell types, including epithelial and innate immune cells, significantly limits tumor growth and progression.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Acriflavina/administración & dosificación , Acriflavina/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Translocador Nuclear del Receptor de Aril Hidrocarburo/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Transducción de Señal/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
UNLABELLED: Intratumoral hypoxia and expression of hypoxia-inducible factor-1α (HIF-1α) correlate with metastasis and poor survival in patients with sarcoma. We show here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF-1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF-1α or PLOD2 expression disrupts collagen modification, cell migration, and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-Kras(G12D/+); Trp53(fl/fl) murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF-1α-deficient tumors, and analysis of human sarcomas reveals elevated HIF1A and PLOD2 expression in metastatic primary lesions. Pharmacologic inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF-1α controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination. SIGNIFICANCE: Undifferentiated pleomorphic sarcoma (UPS) is a commonly diagnosed and particularly aggressive sarcoma subtype in adults, which frequently and fatally metastasizes to the lung. Here, we show the potential use of a novel therapeutic target for the treatment of metastatic UPS, specifi cally the collagen-modifying enzyme PLOD2.
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Hipoxia de la Célula , Colágeno/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Minoxidil/farmacología , Metástasis de la Neoplasia , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/antagonistas & inhibidores , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/metabolismo , Sarcoma/patología , Sarcoma/secundario , Animales , Movimiento Celular , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratones , Ratones Transgénicos , Terapia Molecular Dirigida , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/genética , Sarcoma/metabolismo , Sarcoma Experimental/patología , Células Tumorales CultivadasRESUMEN
Cancer cells are characterized by rapid proliferation and require adaptive metabolic responses to allow continued biosynthesis and cell growth in the setting of decreased oxygen (O(2)) and nutrient availability. The hypoxia-inducible factors (HIFs) are a common link between adaptation to low O(2), changes in cancer metabolism, and malignant progression. The HIF-α subunits differentially regulate metabolic enzymes and other key factors involved in glycolysis, changes in redox status, and oxidative phosphorylation. Importantly, metabolic changes can, in turn, regulate HIF activity. Finally, changes in metabolism under hypoxia lead to important crosstalk between cancer cells and the stromal compartment of the microenvironment.
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Factor 1 Inducible por Hipoxia/metabolismo , Hipoxia/metabolismo , Neoplasias/metabolismo , Oxígeno/metabolismo , Animales , Humanos , Fosforilación Oxidativa , Consumo de Oxígeno , Microambiente TumoralRESUMEN
Hypoxia-inducible factors (HIFs) are oxygen-sensitive transcription factors that allow adaptation to hypoxic environments. HIFs function in the cellular response to stress: metabolic, hypoxic, or inflammatory. Metabolic changes occur during tumorigenesis that are, in part, under hypoxia and HIF regulation. Additionally, inflammatory signaling and infiltration secondary to hypoxia are clear drivers of tumor progression. HIF-1α and HIF-2α have opposing and occasionally overlapping roles in both tumor cells and inflammatory cells within the tumor microenvironment and crosstalk between these populations has clear effects on tumor metabolism, inflammation, and progression. It is becoming increasingly apparent that HIFs are one common link between hypoxia, chronic inflammation, metabolic adaptation, and tumor progression through its function in macrophages during cancer development.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Transformación Celular Neoplásica/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/metabolismo , Neoplasias/metabolismo , Animales , Hipoxia de la Célula , Transformación Celular Neoplásica/inmunología , Humanos , Neoplasias/inmunología , Neoplasias/patología , Estrés Fisiológico , Microambiente TumoralRESUMEN
Citrate is a critical metabolite required to support both mitochondrial bioenergetics and cytosolic macromolecular synthesis. When cells proliferate under normoxic conditions, glucose provides the acetyl-CoA that condenses with oxaloacetate to support citrate production. Tricarboxylic acid (TCA) cycle anaplerosis is maintained primarily by glutamine. Here we report that some hypoxic cells are able to maintain cell proliferation despite a profound reduction in glucose-dependent citrate production. In these hypoxic cells, glutamine becomes a major source of citrate. Glutamine-derived α-ketoglutarate is reductively carboxylated by the NADPH-linked mitochondrial isocitrate dehydrogenase (IDH2) to form isocitrate, which can then be isomerized to citrate. The increased IDH2-dependent carboxylation of glutamine-derived α-ketoglutarate in hypoxia is associated with a concomitant increased synthesis of 2-hydroxyglutarate (2HG) in cells with wild-type IDH1 and IDH2. When either starved of glutamine or rendered IDH2-deficient by RNAi, hypoxic cells are unable to proliferate. The reductive carboxylation of glutamine is part of the metabolic reprogramming associated with hypoxia-inducible factor 1 (HIF1), as constitutive activation of HIF1 recapitulates the preferential reductive metabolism of glutamine-derived α-ketoglutarate even in normoxic conditions. These data support a role for glutamine carboxylation in maintaining citrate synthesis and cell growth under hypoxic conditions.