Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1β

Development ◽  
2002 ◽  
Vol 129 (8) ◽  
pp. 1829-1838 ◽  
Author(s):  
Catherine Coffinier ◽  
Lionel Gresh ◽  
Laurence Fiette ◽  
François Tronche ◽  
Günther Schütz ◽  
...  
Keyword(s):  
Bile Duct ◽  
Target Genes ◽  
Acid Oxidation ◽  
Visceral Endoderm ◽  
Targeted Deletion ◽  
Intrahepatic Bile Ducts ◽  
Hepatocyte Metabolism ◽  
Essential Function ◽  
Severe Jaundice ◽  
Embryonic Death

The inactivation of the Hnf1β gene identified an essential role in epithelial differentiation of the visceral endoderm and resulted in early embryonic death. In the present study, we have specifically inactivated this gene in hepatocytes and bile duct cells using the Cre/loxP system. Mutant animals exhibited severe jaundice caused by abnormalities of the gallbladder and intrahepatic bile ducts (IHBD). The paucity of small IHBD was linked to a failure in the organization of duct structures during liver organogenesis, suggesting an essential function of Hnf1b in bile duct morphogenesis. Mutant mice also lacked interlobular arteries. As HNF1β is not expressed in these cells, it further emphasizes the link between arterial and biliary formation. Hepatocyte metabolism was also affected and we identified hepatocyte-specific HNF1β target genes involved in bile acids sensing and in fatty acid oxidation.

scholarly journals Identifying Personalized Metabolic Signatures in Breast Cancer

Metabolites ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 20
Author(s):  
Priyanka Baloni ◽  
Wikum Dinalankara ◽  
John C. Earls ◽  
Theo A. Knijnenburg ◽  
Donald Geman ◽  
...  
Keyword(s):  
Drug Targets ◽  
Metabolic Networks ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Metabolic Reprogramming ◽  
The Cancer Genome Atlas ◽  
Estrogen Metabolism ◽  
Acid Oxidation ◽  
A Genome ◽  
Context Specific

Cancer cells are adept at reprogramming energy metabolism, and the precise manifestation of this metabolic reprogramming exhibits heterogeneity across individuals (and from cell to cell). In this study, we analyzed the metabolic differences between interpersonal heterogeneous cancer phenotypes. We used divergence analysis on gene expression data of 1156 breast normal and tumor samples from The Cancer Genome Atlas (TCGA) and integrated this information with a genome-scale reconstruction of human metabolism to generate personalized, context-specific metabolic networks. Using this approach, we classified the samples into four distinct groups based on their metabolic profiles. Enrichment analysis of the subsystems indicated that amino acid metabolism, fatty acid oxidation, citric acid cycle, androgen and estrogen metabolism, and reactive oxygen species (ROS) detoxification distinguished these four groups. Additionally, we developed a workflow to identify potential drugs that can selectively target genes associated with the reactions of interest. MG-132 (a proteasome inhibitor) and OSU-03012 (a celecoxib derivative) were the top-ranking drugs identified from our analysis and known to have anti-tumor activity. Our approach has the potential to provide mechanistic insights into cancer-specific metabolic dependencies, ultimately enabling the identification of potential drug targets for each patient independently, contributing to a rational personalized medicine approach.

SGLT2 inhibitors as calorie restriction-mimetics: insights on longevity pathways and age-related diseases

Endocrinology ◽  
2021 ◽  
Author(s):  
Caroline W S Hoong ◽  
Marvin W J Chua
Keyword(s):  
Calorie Restriction ◽  
Stress Resistance ◽  
Target Genes ◽  
Metabolic Diseases ◽  
Vascular Inflammation ◽  
Sglt2 Inhibitors ◽  
Acid Oxidation ◽  
The Metabolic Syndrome ◽  
Age Related ◽  
Energy Deprivation

Abstract SGLT2 inhibitors induce glycosuria, reduce insulin levels, promote fatty acid oxidation and ketogenesis. By promoting a nutrient deprivation state, SGLT2 inhibitors upregulate the energy deprivation sensors AMPK and SIRT1, inhibit the nutrient sensors mTOR and insulin/IGF-1, and modulate the closely-linked HIF-2α/HIF-1α pathways. Phosphorylation of AMPK and upregulation of adiponectin and PPAR-α favour a reversal of the metabolic syndrome which have been linked to suppression of chronic inflammation. Downregulation of insulin/IGF1 pathways and mTOR signalling from a reduction in glucose and circulating amino acids promote cellular repair mechanisms including autophagy and proteostasis which confer cellular stress resistance and attenuate cellular senescence. SIRT1, another energy sensor activated by NAD+ in nutrient-deficient states, is reciprocally activated by AMPK, and can deacetylate and activate transcription factors such as PCG-1α, TFAM and NRF2 that regulate mitochondrial biogenesis. FOXO3 transcription factor which target genes in stress resistance, is also activated by AMPK and SIRT1. Modulation of these pathways by SGLT2 inhibitors have been shown to alleviate metabolic diseases, attenuate vascular inflammation and arterial stiffness, improve mitochondrial function and reduce oxidative stress-induced tissue damage. Compared to other calorie restriction mimetics such as metformin, rapamycin, resveratrol and NAD+ precursors, SGLT2 inhibitors appear to be the most promising in the treatment of ageing-related diseases, due to its regulation of multiple longevity pathways that closely resemble that achieved by calorie restriction, and their established efficacy in reduction in cardiovascular events and all-cause mortality. Evidence is compelling for the role of SGLT2 inhibitors as a calorie restriction mimetic in anti-ageing therapeutics.

ATGL-mediated triglyceride turnover and the regulation of mitochondrial capacity in skeletal muscle

2015 ◽  
Vol 308 (11) ◽  
pp. E960-E970 ◽  
Author(s):  
Ruth C. R. Meex ◽  
Andrew J. Hoy ◽  
Rachael M. Mason ◽  
Sheree D. Martin ◽  
Sean L. McGee ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Lipid Droplets ◽  
Target Genes ◽  
Control Point ◽  
Hormone Sensitive Lipase ◽  
Acid Oxidation ◽  
Minor Importance ◽  
Transcriptional Responses ◽  
Mitochondrial Capacity

Emerging evidence indicates that skeletal muscle lipid droplets are an important control point for intracellular lipid homeostasis and that regulating fatty acid fluxes from lipid droplets might influence mitochondrial capacity. We used pharmacological blockers of the major triglyceride lipases, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase, to show that a large proportion of the fatty acids that are transported into myotubes are trafficked through the intramyocellular triglyceride pool. We next tested whether increasing lipolysis from intramyocellular lipid droplets could activate transcriptional responses to enhance mitochondrial and fatty acid oxidative capacity. ATGL was overexpressed by adenoviral and adenoassociated viral infection in C2C12 myotubes and the tibialis anterior muscle of C57Bl/6 mice, respectively. ATGL overexpression in C2C12 myotubes increased lipolysis, which was associated with increased peroxisome proliferator-activated receptor (PPAR)-∂ activity, transcriptional upregulation of some PPAR∂ target genes, and enhanced mitochondrial capacity. The transcriptional responses were specific to ATGL actions and not a generalized increase in fatty acid flux in the myotubes. Marked ATGL overexpression (20-fold) induced modest molecular changes in the skeletal muscle of mice, but these effects were not sufficient to alter fatty acid oxidation. Together, these data demonstrate the importance of lipid droplets for myocellular fatty acid trafficking and the capacity to modulate mitochondrial capacity by enhancing lipid droplet lipolysis in vitro; however, this adaptive program is of minor importance when superimposing the normal metabolic stresses encountered in free-moving animals.

scholarly journals Anomalous choledocho-pancretic ductal junction in a choledochal cyst: A case report

2004 ◽  
Vol 132 (5-6) ◽  
pp. 179-181
Author(s):  
Miodrag Jovanovic ◽  
Dragoljub Bilanovic ◽  
Radoje Colovic ◽  
Nikica Grubor ◽  
Milenko Ugljesic
Keyword(s):  
Bile Duct ◽  
Choledochal Cyst ◽  
Bile Ducts ◽  
Postoperative Recovery ◽  
Biliary Colic ◽  
Duodenal Wall ◽  
Choledochal Cysts ◽  
Bile Duct Wall ◽  
Intrahepatic Bile Ducts ◽  
Inflammatory Changes

Choledochal cysts are rare congenital anomalies, mostly detected in adults. Pathogenesis of these cysts seems to be in anomalous junction between pancreatic and common bile duct, above the papillary sphincterand outside of the duodenal wall. The absence of the sphincter above the junction is followed by reflux of the pancreatic juice into the bile duct leading to dilatation and fibrous changes of bile duct wall. A 38-year-old female is presented in whom a choledochal cyst was found 11 years earlier, during the operation performed for obstructive jaundice, when cystojejunostomy with Roux-en Y jejunal limb was carried out. In February 1990, she was admitted to our Institution for jaundice and biliary colic. The patient was reoperated. Operative cholangiography showed an anomalous pancreatobiliary junction, choledochal cyst, dilated cystic duct and moderate dilatation of intrahepatic bile ducts. Cholecystectomy, desanastomosis with partial excision of choledochal cyst, and retrocolic choledochojejunostomy with the same Roux-en-Y jejunal limb were performed. Total excision of choledochal cyst was too risky due to chronic inflammatory changes in the hepatoduodenal ligament. Postoperative recovery was uneventful and the patient remained symptom-free so far.

scholarly journals Biliobronchial fistula secondary to percutaneous dilatation of the benign biliary stricture

2012 ◽  
Vol 140 (11-12) ◽  
pp. 772-776
Author(s):  
Radoje Colovic ◽  
Nikica Grubor ◽  
Marko Kaitovic ◽  
Stojan Latincic ◽  
Natasa Colovic
Keyword(s):  
Bile Duct ◽  
Biliary Stricture ◽  
Surgical Reconstruction ◽  
Benign Biliary Stricture ◽  
Benign Stricture ◽  
Intrahepatic Bile Ducts ◽  
Percutaneous Dilatation ◽  
Grade Ii ◽  
Benign Bile Duct Stricture ◽  
Duct Stricture

Introduction. Biliobronchial fistula is rare. Very rarely it may be congenital, more frequently it is acquired as a complication of the hydatide cyst of the liver, pyogenic abscess, serious trauma and resection of the liver as well as recurrent cholangitis due to benign bile duct stricture or cholangiolithiasis. The main causes of the biliobronchial fistula are billiary obstruction and infectious lesion (abscess) in the liver. Case Outline. We present a 56-year-old man with benign stricture of the hepaticojejunostomy performed after operative common bile duct injury, who developed biliobronchial fistula following repeated percutaneous drainage of the liver abscess and percutaneous dilatation of the strictured anastomosis. Over the years the patient developed atrophy/hypertrophy complex, portal hypertension, grade II esophageal varicosities, ascites and splenomegaly. Although biliobronchial fistula was solved by a successful surgical reconstruction (new wide hepaticojejunostomy), the operation had a limited value as it was performed late after permanent lesions of the liver and intrahepatic bile ducts had already developed. Conclusion. Surgical reconstruction of strictured biliodigestive anastomosis should be considered on time as a possibly better solution than percutaneous dilatation. According to the authors? knowledge, a similar case of biliobronchial fistula as a complication of percutaneous dilatation of the benign biliary stricture has not been reported before in the literature.

scholarly journals YAP Activation and Implications in Patients and a Mouse Model of Biliary Atresia

2021 ◽  
Vol 8 ◽  
Author(s):  
Chao Zheng ◽  
Jiaqian Luo ◽  
Yifan Yang ◽  
Rui Dong ◽  
Fa-Xing Yu ◽  
...  
Keyword(s):  
Bile Duct ◽  
Liver Fibrosis ◽  
Mouse Model ◽  
Biliary Atresia ◽  
Signaling Pathway ◽  
Target Genes ◽  
Hippo Signaling ◽  
Mice Model ◽  
Hippo Signaling Pathway ◽  
Ductal Cells

Background and Aim: Biliary atresia (BA), an inflammatory destruction of the bile ducts, leads to liver fibrosis in infants and accounts for half of cases undergoing pediatric liver transplantation. Yes-associated protein (YAP), an effector of the Hippo signaling pathway, is critical in maintaining identities of bile ductal cells. Here, we evaluated the expression of YAP and YAP target genes in BA livers and a rhesus rotavirus (RRV)-induced BA mice model.Methods: Liver specimens collected from 200 BA patients were compared with those of 30 non-BA patients. Model mice liver tissues were also collected. The expression of YAP and YAP target genes were measured by transfection, RNA-seq, immunohistochemistry, immunoblot, and quantitative PCR. Masson's trichrome staining and the Biliary Atresia Research Consortium (BARC) system were utilized to score liver fibrosis status.Results: The expression of YAP is elevated and positively correlated with fibrosis in BA livers. Moreover, ANKRD1, which is identified as the target gene of YAP, is also highly expressed in BA livers. Consistent with clinical data, YAP and ANKRD1 are significantly upregulated in RRV-induced BA mouse model.Conclusions: YAP expression is closely correlated with the bile duct hyperplasia and liver fibrosis, and may serve as an indicator for liver fibrosis and BA progression. This study indicates an involvement of the Hippo signaling pathway in the development of BA, and the YAP induced ANKRD1 expression may also be related to bile duct hyperplasia in BA. This provides a new direction for more in-depth exploration of the etiology and pathogenesis of biliary atresia.

Drug-Induced Vanishing Bile Duct Syndrome: From Pathogenesis to Diagnosis and Therapeutics

2021 ◽  
Author(s):  
Fernando Bessone ◽  
Nidia Hernández ◽  
Mario Tanno ◽  
Marcelo G. Roma
Keyword(s):  
Bile Duct ◽  
Diagnostic Tools ◽  
Drug Induced ◽  
Vanishing Bile Duct Syndrome ◽  
Beneficial Effects ◽  
Intrahepatic Bile Ducts ◽  
Chronic Cholestasis ◽  
Vanishing Bile Duct ◽  
Therapeutic Alternatives ◽  
Duct Syndrome

AbstractThe most concerned issue in the context of drug/herb-induced chronic cholestasis is vanishing bile duct syndrome. The progressive destruction of intrahepatic bile ducts leading to ductopenia is usually not dose dependent, and has a delayed onset that should be suspected when abnormal serum cholestasis enzyme levels persist despite drug withdrawal. Immune-mediated cholangiocyte injury, direct cholangiocyte damage by drugs or their metabolites once in bile, and sustained exposure to toxic bile salts when biliary epithelium protective defenses are impaired are the main mechanisms of cholangiolar damage. Current therapeutic alternatives are scarce and have not shown consistent beneficial effects so far. This review will summarize the current literature on the main diagnostic tools of ductopenia and its histological features, and the differential diagnostic with other ductopenic diseases. In addition, pathomechanisms will be addressed, as well as the connection between them and the supportive and curative strategies for ductopenia management.

scholarly journals SIRT3 deficiency exacerbates fatty liver by attenuating the HIF1α-LIPIN 1 pathway and increasing CD36 through Nrf2

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Emma Barroso ◽  
Rosalía Rodríguez-Rodríguez ◽  
Mohammad Zarei ◽  
Javier Pizarro-Degado ◽  
Anna Planavila ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Redox Status ◽  
Acid Oxidation ◽  
Standard Diet ◽  
Peroxisome Proliferator ◽  
Lipid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Vldl Receptor

Abstract Background Deficiency of mitochondrial sirtuin 3 (SIRT3), a NAD+-dependent protein deacetylase that maintains redox status and lipid homeostasis, contributes to hepatic steatosis. In this study, we investigated additional mechanisms that might play a role in aggravating hepatic steatosis in Sirt3-deficient mice fed a high-fat diet (HFD). Methods Studies were conducted in wild-type (WT) and Sirt3−/− mice fed a standard diet or a HFD and in SIRT3-knockdown human Huh-7 hepatoma cells. Results Sirt3−/− mice fed a HFD presented exacerbated hepatic steatosis that was accompanied by decreased expression and DNA-binding activity of peroxisome proliferator-activated receptor (PPAR) α and of several of its target genes involved in fatty acid oxidation, compared to WT mice fed the HFD. Interestingly, Sirt3 deficiency in liver and its knockdown in Huh-7 cells resulted in upregulation of the nuclear levels of LIPIN1, a PPARα co-activator, and of the protein that controls its levels and localization, hypoxia-inducible factor 1α (HIF-1α). These changes were prevented by lipid exposure through a mechanism that might involve a decrease in succinate levels. Finally, Sirt3−/− mice fed the HFD showed increased levels of some proteins involved in lipid uptake, such as CD36 and the VLDL receptor. The upregulation in CD36 was confirmed in Huh-7 cells treated with a SIRT3 inhibitor or transfected with SIRT3 siRNA and incubated with palmitate, an effect that was prevented by the Nrf2 inhibitor ML385. Conclusion These findings demonstrate new mechanisms by which Sirt3 deficiency contributes to hepatic steatosis. Graphical abstract

scholarly journals RNF216 is essential for spermatogenesis and male fertility†

2019 ◽  
Vol 100 (5) ◽  
pp. 1132-1134 ◽  
Author(s):  
Ashley F Melnick ◽  
Yuen Gao ◽  
Jiali Liu ◽  
Deqiang Ding ◽  
Alicia Predom ◽  
...  
Keyword(s):  
Male Fertility ◽  
Mammalian Species ◽  
Critical Role ◽  
Ring Finger ◽  
Gonadal Development ◽  
Cellular Protein ◽  
Ring Finger Protein ◽  
Targeted Deletion ◽  
Finger Protein ◽  
Essential Function

Abstract Ring finger protein 216 (RNF216) belongs to the RING family of E3 ubiquitin ligases that are involved in cellular protein degradation. Mutations in human Rnf216 gene have been identified in Gordon Holmes syndrome, which is defined by ataxia, dementia, and hypogonadotropism. However, the gene function of Rnf216 in mammalian species remains unknown. Here, we show that targeted deletion of Rnf216 in mice results in disruption in spermatogenesis and male infertility. RNF216 is not required for female fertility. These findings reveal an essential function of RNF216 in spermatogenesis and male fertility and suggest a critical role for RNF216 in human gonadal development.

scholarly journals Case Report: Kryptonite—A Rare Case of Left-Sided Bilothorax in a Sickle Cell Patient

2019 ◽  
Vol 2019 ◽  
pp. 1-4
Author(s):  
Vikas D. Reddy ◽  
Anas Al-Khateeb ◽  
Muhammad Hussain ◽  
Varun Patel ◽  
Muqueet Kadri ◽  
...  
Keyword(s):  
Bile Duct ◽  
Common Bile Duct ◽  
Pleural Fluid ◽  
Sickle Cell ◽  
Serum Bilirubin ◽  
Magnetic Resonance Cholangiopancreatography ◽  
Endoscopic Retrograde ◽  
Distal Common Bile Duct ◽  
Intrahepatic Bile Ducts ◽  
Sickle Cell Crisis

Bilothorax is a rare cause of an exudative pleural effusion. The diagnosis is confirmed by a pleural fluid to serum bilirubin ratio of greater than 1. Typically, bilothorax presents as a right-sided effusion due to its proximity to the liver and biliary system. Herein, we present a case of isolated left-sided bilothorax in a 43-year-old female admitted with sickle cell crisis. Only one other case of isolated spontaneous left-sided bilothorax has been described in the literature. A thoracentesis performed on admission demonstrated greenish fluid and bilothorax was suspected, with a pleural fluid to serum bilirubin ratio greater than 1 confirming the diagnosis. A magnetic resonance cholangiopancreatography (MRCP) showed an abnormal 90-degree acute angulation in the mid-to-distal common bile duct with proximal common bile duct and intrahepatic bile ducts dilation. This was further confirmed with an endoscopic retrograde cholangiopancreatography (ERCP), which did not reveal any extravasation of contrast into the left pleural space. Ultimately, despite the use of various modalities, no definitive cause of bilothorax was identified. Postthoracentesis imaging revealed evidence of fibrothorax, a direct and permanent complication of bilothorax. The presence of an isolated left-sided bilothorax, along with the lack of a confirmed etiology, makes this case unique.

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