β-catenin-activated hepatocellular carcinomas are addicted to fatty acids

Gut ◽  
2018 ◽  
Vol 68 (2) ◽  
pp. 322-334 ◽  
Author(s):  
Nadia Senni ◽  
Mathilde Savall ◽  
David Cabrerizo Granados ◽  
Marie-Clotilde Alves-Guerra ◽  
Chiara Sartor ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Target Therapy ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Primary Hepatocytes ◽  
Knock Out ◽  
Metabolic Fluxes ◽  
Hepatocellular Carcinomas ◽  
Knock Out Mice

ObjectivesCTNNB1-mutated hepatocellular carcinomas (HCCs) constitute a major part of human HCC and are largely inaccessible to target therapy. Yet, little is known about the metabolic reprogramming induced by β-catenin oncogenic activation in the liver. We aimed to decipher such reprogramming and assess whether it may represent a new avenue for targeted therapy of CTNNB1-mutated HCC.DesignWe used mice with hepatocyte-specific oncogenic activation of β-catenin to evaluate metabolic reprogramming using metabolic fluxes on tumourous explants and primary hepatocytes. We assess the role of Pparα in knock-out mice and analysed the consequences of fatty acid oxidation (FAO) using etomoxir. We explored the expression of the FAO pathway in an annotated human HCC dataset.Resultsβ-catenin-activated HCC were not glycolytic but intensively oxidised fatty acids. We found that Pparα is a β-catenin target involved in FAO metabolic reprograming. Deletion of Pparα was sufficient to block the initiation and progression of β-catenin-dependent HCC development. FAO was also enriched in human CTNNB1-mutated HCC, under the control of the transcription factor PPARα.ConclusionsFAO induced by β-catenin oncogenic activation in the liver is the driving force of the β-catenin-induced HCC. Inhibiting FAO by genetic and pharmacological approaches blocks HCC development, showing that inhibition of FAO is a suitable therapeutic approach for CTNNB1-mutated HCC.

scholarly journals Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xin Ding ◽  
Jin Wang ◽  
Miaoxin Huang ◽  
Zhangpeng Chen ◽  
Jing Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Knock Out ◽  
Classical Complement Pathway ◽  
Synaptic Remodeling ◽  
The Central Nervous System ◽  
System Activation ◽  
Knock Out Mice ◽  
Synaptic Pruning

AbstractMicroglia play a key role in regulating synaptic remodeling in the central nervous system. Activation of classical complement pathway promotes microglia-mediated synaptic pruning during development and disease. CD47 protects synapses from excessive pruning during development, implicating microglial SIRPα, a CD47 receptor, in synaptic remodeling. However, the role of microglial SIRPα in synaptic pruning in disease remains unclear. Here, using conditional knock-out mice, we show that microglia-specific deletion of SIRPα results in decreased synaptic density. In human tissue, we observe that microglial SIRPα expression declines alongside the progression of Alzheimer’s disease. To investigate the role of SIRPα in neurodegeneration, we modulate the expression of microglial SIRPα in mouse models of Alzheimer’s disease. Loss of microglial SIRPα results in increased synaptic loss mediated by microglia engulfment and enhanced cognitive impairment. Together, these results suggest that microglial SIRPα regulates synaptic pruning in neurodegeneration.

scholarly journals REST is a major negative regulator of endocrine differentiation during pancreas organogenesis

2021 ◽  
Author(s):  
Meritxell Rovira ◽  
Goutham Atla ◽  
Miguel Angel Maestro ◽  
Vane Grau ◽  
Javier García-Hurtado ◽  
...  
Keyword(s):  
Endocrine Cells ◽  
Negative Regulator ◽  
Β Cell ◽  
Knock Out ◽  
Endocrine Differentiation ◽  
Conditional Allele ◽  
Embryonic Pancreas ◽  
Pancreatic Endocrine Cells ◽  
Knock Out Mice

SUMMARYUnderstanding genomic regulatory mechanisms of pancreas differentiation is relevant to the pathophysiology of diabetes mellitus, and to the development of replacement therapies. Numerous transcription factors promote β cell differentiation, although less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrine gene programs in the embryonic pancreas. However, pancreaticRestknock-out mice failed to show increased numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we now observe a marked increase in the formation of pancreatic endocrine cells. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts, and induced β-cell specific genes in human adult duct-derived organoids. Finally, we define REST genomic programs that suppress pancreatic endocrine differentiation. These results establish a crucial role of REST as a negative regulator of pancreatic endocrine differentiation.

scholarly journals Anatomical, Physiological, and Pharmacological Characteristics of Histidine Decarboxylase Knock-Out Mice: Evidence for the Role of Brain Histamine in Behavioral and Sleep–Wake Control

2002 ◽  
Vol 22 (17) ◽  
pp. 7695-7711 ◽  
Author(s):  
Régis Parmentier ◽  
Hiroshi Ohtsu ◽  
Zahia Djebbara-Hannas ◽  
Jean-Louis Valatx ◽  
Takehiko Watanabe ◽  
...  
Keyword(s):  
Histidine Decarboxylase ◽  
Brain Histamine ◽  
Knock Out ◽  
Knock Out Mice

scholarly journals Ataxin-2 (Atxn2)-Knock-Out Mice Show Branched Chain Amino Acids and Fatty Acids Pathway Alterations

2016 ◽  
Vol 15 (5) ◽  
pp. 1728-1739 ◽  
Author(s):  
David Meierhofer ◽  
Melanie Halbach ◽  
Nesli Ece Şen ◽  
Suzana Gispert ◽  
Georg Auburger
Keyword(s):  
Amino Acids ◽  
Fatty Acids ◽  
Branched Chain Amino Acids ◽  
Knock Out ◽  
Ataxin 2 ◽  
Branched Chain ◽  
Knock Out Mice

scholarly journals Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3302
Author(s):  
Kaja Blagotinšek Cokan ◽  
Žiga Urlep ◽  
Gregor Lorbek ◽  
Madlen Matz-Soja ◽  
Cene Skubic ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcription Factors ◽  
Plasma Cholesterol ◽  
Metabolic Reprogramming ◽  
Receptor Interaction ◽  
Blood Parameter ◽  
Knock Out ◽  
Liver Cancers ◽  
Knock Out Mice ◽  
Post Menopausal

While the role of cholesterol in liver carcinogenesis remains controversial, hepatocellular carcinoma generally prevails in males. Herein, we uncover pathways of female-prevalent progression to hepatocellular carcinoma due to chronic repression of cholesterogenic lanosterol 14α-demethylase (CYP51) in hepatocytes. Tumors develop in knock-out mice after year one, with 2:1 prevalence in females. Metabolic and transcription factor networks were deduced from the liver transcriptome data, combined by sterol metabolite and blood parameter analyses, and interpreted with relevance to humans. Female knock-outs show increased plasma cholesterol and HDL, dampened lipid-related transcription factors FXR, LXRα:RXRα, and importantly, crosstalk between reduced LXRα and activated TGF-β signalling, indicating a higher susceptibility to HCC in aging females. PI3K/Akt signalling and ECM-receptor interaction are common pathways that are disturbed by sex-specific altered genes. Additionally, transcription factors (SOX9)2 and PPARα were recognized as important for female hepatocarcinogenesis, while overexpressed Cd36, a target of nuclear receptor RORC, is a new male-related regulator of ECM-receptor signalling in hepatocarcinogenesis. In conclusion, we uncover the sex-dependent metabolic reprogramming of cholesterol-related pathways that predispose for hepatocarcinogenesis in aging females. This is important in light of increased incidence of liver cancers in post-menopausal women.

Involvement of E-selectin in recruitment of endothelial progenitor cells and angiogenesis in ischemic muscle

Blood ◽  
2007 ◽  
Vol 110 (12) ◽  
pp. 3891-3899 ◽  
Author(s):  
Il-Young Oh ◽  
Chang-Hwan Yoon ◽  
Jin Hur ◽  
Ji-Hyun Kim ◽  
Tae-Youn Kim ◽  
...  
Keyword(s):  
Local Treatment ◽  
Mouse Bone Marrow ◽  
Endothelial Progenitor ◽  
Blocking Antibody ◽  
Knock Out ◽  
Ischemic Limb ◽  
Injection Mechanism ◽  
Knock Out Mice ◽  
Interfering Rna

Abstract E-selectin plays critical roles in tethering leukocytes to endothelial cells (ECs). We studied the role of E-selectin in endothelial progenitor cell (EPC) homing and vasculogenesis. After ischemia, the expression of E-selectin on ECs peaked 6 to 12 hours and returned to baseline at 24 hours, whereas the level of soluble E-selectin (sE-selectin) in serum increased over 24 hours and remained high at day 7. Mouse bone marrow–derived EPCs expressed not only E-selectin but also its ligand. Homing of circulating EPCs to ischemic limb was significantly impaired in E-selectin knock-out mice, as well as wild-type mice pretreated with blocking antibody against E-selectin, which was rescued by local sE-selectin injection. Mechanism for this is that sE-selectin stimulated not only ECs to express ICAM-1, but also EPCs to secrete interleukin-8 (IL-8), leading to enhanced migration and incorporation to ECs capillary formation. In therapeutic aspect, local treatment with sE-selectin enhanced efficacy of EPC transplantation for vasculogenesis and salvage of ischemic limb. Conversely, when E-selectin was knocked down by E-selectin small interfering RNA, blood flow recovery after EPC transplantation was significantly impaired. But this impaired vasculogenesis was rescued by sE-selectin. In conclusion, these data demonstrate E-selectin is a pivotal molecule for EPCs' homing to ischemic limb and vasculogenesis.

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