RESUMO
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.
RESUMO
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.
Assuntos
Refluxo Gastroesofágico , Gastroenteropatias , Hepatopatia Gordurosa não Alcoólica , Humanos , Obesidade/complicações , Obesidade/epidemiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/terapia , Gastroenteropatias/etiologia , Gastroenteropatias/terapiaRESUMO
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.
Assuntos
Ascite/etiologia , Derivação Ventriculoperitoneal/efeitos adversos , Adulto , Ascite/diagnóstico , Ascite/terapia , Líquido Ascítico/metabolismo , Feminino , Humanos , Hidrocefalia/terapia , Síndrome de Loeys-Dietz , Derivação Peritoneovenosa , Albumina Sérica/metabolismoRESUMO
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.
Assuntos
Doença Hepática Terminal/cirurgia , Cardiopatias/mortalidade , Transplante de Fígado , Complicações Pós-Operatórias/mortalidade , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de TempoRESUMO
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.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hipóxia Celular/fisiologia , Colite/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Macrófagos/imunologia , Neutrófilos/imunologia , Proteína Amiloide A Sérica/análise , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Transporte/genética , Colite/induzido quimicamente , Colo/citologia , Colo/imunologia , Colo/patologia , Modelos Animais de Doenças , Proteínas Fetais/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Leucócitos Mononucleares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genéticaRESUMO
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.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Acriflavina/administração & dosagem , Acriflavina/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Hipóxia Celular , Colágeno/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Minoxidil/farmacologia , Metástase Neoplásica , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/antagonistas & inibidores , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/metabolismo , Sarcoma/patologia , Sarcoma/secundário , Animais , Movimento Celular , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Camundongos Transgênicos , Terapia de Alvo Molecular , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/genética , Sarcoma/metabolismo , Sarcoma Experimental/patologia , Células Tumorais CultivadasRESUMO
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.
Assuntos
Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Neoplasias/metabolismo , Oxigênio/metabolismo , Animais , Humanos , Fosforilação Oxidativa , Consumo de Oxigênio , Microambiente TumoralRESUMO
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.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Transformação Celular Neoplásica/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/metabolismo , Neoplasias/metabolismo , Animais , Hipóxia Celular , Transformação Celular Neoplásica/imunologia , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Estresse Fisiológico , Microambiente TumoralRESUMO
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.