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HNF4α

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https://www.readbyqxmd.com/read/29150932/high-fat-diet-induced-oxidative-stress-blocks-hepatocyte-nuclear-factor-4%C3%AE-and-leads-to-hepatic-steatosis-in-mice
#1
Dongsheng Yu, Gang Chen, Minglin Pan, Jia Zhang, Wenping He, Yang Liu, Xue Nian, Liang Sheng, Bin Xu
Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease with manifestation of over-accumulation of fat in liver. Increasing evidences indicate that NAFLD may be in part caused by malfunction of very low density lipoprotein (VLDL) secretion. Hepatocyte nuclear factor 4α (HNF4α), a nuclear receptor protein, plays an important role in sustain hepatic lipid homeostasis via transcriptional regulation of genes involved in secretion of VLDL, such as apolipoprotein B (ApoB). However, the exact functional change of HNF4α in NAFLD remains to be elucidated...
November 18, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29129613/pgc-1%C3%AE-functions-as-a-co-suppressor-of-xbp1s-to-regulate-glucose-metabolism
#2
Jaemin Lee, Mario Andrés Salazar Hernández, Thomas Auen, Patrick Mucka, Justin Lee, Umut Ozcan
OBJECTIVE: Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) promotes hepatic gluconeogenesis by activating HNF4α and FoxO1. PGC-1α expression in the liver is highly elevated in obese and diabetic conditions, leading to increased hepatic glucose production. We previously showed that the spliced form of X-box binding protein 1 (XBP1s) suppresses FoxO1 activity and hepatic gluconeogenesis. The shared role of PGC-1α and XBP1s in regulating FoxO1 activity and gluconeogenesis led us to investigate the probable interaction between PGC-1α and XBP1s and its role in glucose metabolism...
October 28, 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29091211/influence-of-abcb11-and-hnf4%C3%AE-genes-on-daclatasvir-plasma-concentration-preliminary-pharmacogenetic-data-from-the-kineti-c-study
#3
Jessica Cusato, Amedeo De Nicolò, Lucio Boglione, Fabio Favata, Alessandra Ariaudo, Simone Mornese Pinna, Federica Guido, Valeria Avataneo, Chiara Carcieri, Giuseppe Cariti, Giovanni Di Perri, Antonio D'Avolio
Background: Daclatasvir is an inhibitor of HCV non-structural 5A protein and is a P-glycoprotein substrate. Pharmacogenetics has had a great impact on previous anti-HCV therapies, particularly considering the association of IL-28B polymorphisms with dual therapy outcome. Objectives: We investigated the association between daclatasvir plasma concentrations at 2 weeks and 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCB11 and HNF4α)...
October 1, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29072691/phosphoprotein-enriched-in-diabetes-ped-pea15-promotes-migration-in-hepatocellular-carcinoma-and-confers-resistance-to-sorafenib
#4
Cristina Quintavalle, Sravanth Kumar Hindupur, Luca Quagliata, Pierlorenzo Pallante, Cecilia Nigro, Gerolama Condorelli, Jesper Bøje Andersen, Katrin Elisabeth Tagscherer, Wilfried Roth, Francesco Beguinot, Markus Hermann Heim, Charlotte Kiu Yan Ng, Salvatore Piscuoglio, Matthias Sebastian Matter
Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related death with limited treatment options and frequent resistance to sorafenib, the only drug currently approved for first-line therapy. Therefore, better understanding of HCC tumor biology and its resistance to treatment is urgently needed. Here, we analyzed the role of phosphoprotein enriched in diabetes (PED) in HCC. PED has been shown to regulate cell proliferation, apoptosis and migration in several types of cancer. However, its function in HCC has not been addressed yet...
October 26, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29051787/increased-expression-of-hepatocyte-nuclear-factor-4-alpha-transcribed-by-promoter-2-indicates-a-poor-prognosis-in-hepatocellular-carcinoma
#5
Shao-Hang Cai, Shi-Xun Lu, Li-Li Liu, Chris Zhiyi Zhang, Jing-Ping Yun
BACKGROUND: Hepatocyte nuclear factor 4 alpha (HNF4α) plays an important role in tumourigenesis. There is growing evidence indicating that HNF4α transcribed by promoter 1 (P1-HNF4α) is expressed at relatively low levels in HCC and its presence predicts a favourable outcome for hepatocellular carcinoma (HCC) patients. However, the role of HNF4α transcribed by promoter 2 (P2-HNF4α) in HCC remains unclear. METHODS: A total of 615 HCC specimens were obtained to construct tissue microarrays and perform immunohistochemistry...
October 2017: Therapeutic Advances in Gastroenterology
https://www.readbyqxmd.com/read/29030272/impact-of-fasting-followed-by-short-term-exposure-to-interleukin-6-on-cytochrome-p450-mrna-in-mice
#6
Martin Krøyer Rasmussen, Lærke Bertholdt, Anders Gudiksen, Henriette Pilegaard, Jakob G Knudsen
The gene expression of the cytochrome P450 (CYP) enzyme family is regulated by numerous factors. Fasting has been shown to induce increased hepatic CYP mRNA in both humans and animals. However, the coordinated regulation of CYP, CYP-regulating transcription factors, and transcriptional co-factors in the liver linking energy metabolism to detoxification has never been investigated. Interleukin-6 (IL-6) has been suggested to be released during fasting and has been shown to regulate CYP expression. The present study investigated the hepatic mRNA content of selected CYP, AhR, CAR, PXR and PPARα in mice fasted for 18h and subsequently exposed to IL-6...
October 10, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29023917/prmt1-and-jmjd6-dependent-arginine-methylation-regulate-hnf4%C3%AE-expression-and-hepatocyte-proliferation
#7
Jie Zhao, Abby Adams, Ben Roberts, Maura O'Neil, Anusha Vittal, Timothy Schmitt, Sean Kumer, Josiah Cox, Zhuan Li, Steven A Weinman, Irina Tikhanovich
Alcohol is a well-established risk factor for hepatocellular carcinoma, but the mechanisms by which it promotes liver cancer are not well understood. Several studies have shown that cellular protein arginine methylation is inhibited by alcohol. Arginine methylation is controlled by the reciprocal activity of protein arginine methyltransferases, primarily PRMT1, and a demethylase JMJD6. The aim of this study was to explore the role of arginine methylation changes in alcohol pathogenesis. We found that PRMT1 activity is inhibited in livers of mice fed with alcohol compared to pair-fed mice...
October 10, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28981086/engineered-fibroblast-growth-factor-19-protects-from-acetaminophen-induced-liver-injury-and-stimulates-aged-liver-regeneration-in-mice
#8
Gloria Alvarez-Sola, Iker Uriarte, Maria U Latasa, Maddalen Jimenez, Marina Barcena-Varela, Eva Santamaría, Raquel Urtasun, Carlos Rodriguez-Ortigosa, Jesús Prieto, Fernando J Corrales, Anna Baulies, Carmen García-Ruiz, Jose C Fernandez-Checa, Pedro Berraondo, Maite G Fernandez-Barrena, Carmen Berasain, Matías A Avila
The liver displays a remarkable regenerative capacity triggered upon tissue injury or resection. However, liver regeneration can be overwhelmed by excessive parenchymal destruction or diminished by pre-existing conditions hampering repair. Fibroblast growth factor 19 (FGF19, rodent FGF15) is an enterokine that regulates liver bile acid and lipid metabolism, and stimulates hepatocellular protein synthesis and proliferation. FGF19/15 is also important for liver regeneration after partial hepatectomy (PH). Therefore recombinant FGF19 would be an ideal molecule to stimulate liver regeneration, but its applicability may be curtailed by its short half-life...
October 5, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28963035/mirna-122-protects-mice-and-human-hepatocytes-from-acetaminophen-toxicity-by-regulating-cytochrome-p450-family-2-subfamily-a-member-2-and-e-member-1-expression
#9
Vivek Chowdhary, Kun-Yu Teng, Sharda Thakral, Bo Zhang, Cho-Hao Lin, Nissar Wani, Lei Bruschweiler-Li, Xiaoli Zhang, Laura James, Dakai Yang, Norman Junge, Rafael Brüschweiler, William M Lee, Kalpana Ghoshal
Acetaminophen toxicity is a leading cause of acute liver failure (ALF). We found that miRNA-122 (miR-122) is down-regulated in liver biopsy specimens of patients with ALF and in acetaminophen-treated mice. A marked decrease in the primary miR-122 expression occurs in mice on acetaminophen overdose because of suppression of its key transactivators, hepatocyte nuclear factor (HNF)-4α and HNF6. More importantly, the mortality rates of male and female liver-specific miR-122 knockout (LKO) mice were significantly higher than control mice when injected i...
September 28, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28943765/lactobacillus-acidophilus-ns1-reduces-phosphoenolpyruvate-carboxylase-expression-by-regulating-hnf4%C3%AE-transcriptional-activity
#10
Sung-Soo Park, Garam Yang, Eungseok Kim
Probiotics have been known to reduce high-fat diet (HFD)-induced metabolic diseases, such as obesity, insulin resistance, and type 2 diabetes. We recently observed that Lactobacillus acidophilus NS1 (LNS1), distinctly suppresses increase of blood glucose levels and insulin resistance in HFD-fed mice. In the present study, we demonstrated that oral administration of LNS1 with HFD feeding to mice significantly reduces hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme in gluconeogenesis which is highly increased by HFD feeding...
2017: Korean Journal for Food Science of Animal Resources
https://www.readbyqxmd.com/read/28943029/generation-of-mouse-and-human-organoid-forming-intestinal-progenitor-cells-by-direct-lineage-reprogramming
#11
Shizuka Miura, Atsushi Suzuki
Intestinal organoids hold great promise as a valuable tool for studying and treating intestinal diseases. The currently available sources of human intestinal organoids, tissue fragments or pluripotent stem cells, involve invasive procedures or complex differentiation protocols, respectively. Here, we show that a set of four transcription factors, Hnf4α, Foxa3, Gata6, and Cdx2, can directly reprogram mouse fibroblasts to acquire the identity of fetal intestine-derived progenitor cells (FIPCs). These induced FIPCs (iFIPCs) form spherical organoids that develop into adult-type budding organoids containing cells with intestinal stem cell properties...
October 5, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28938650/genomic-variants-link-to-hepatitis-c-racial-disparities
#12
Matthew M Yeh, Sarag Boukhar, Benjamin Roberts, Nairanjana Dasgupta, Sayed S Daoud
Chronic liver diseases are one of the major public health issues in United States, and there are substantial racial disparities in liver cancer-related mortality. We previously identified racially distinct alterations in the expression of transcripts and proteins of hepatitis C (HCV)-induced hepatocellular carcinoma (HCC) between Caucasian (CA) and African American (AA) subgroups. Here, we performed a comparative genome-wide analysis of normal vs. HCV+ (cirrhotic state), and normal adjacent tissues (HCCN) vs...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28935574/taurocholate-induces-biliary-differentiation-of-liver-progenitor-cells-causing-hepatic-stellate-cell-chemotaxis-in-the-ductular-reaction-role-in-pediatric-cystic-fibrosis-liver-disease
#13
Katarzyna N Pozniak, Michael A Pearen, Tamara N Pereira, Cynthia S M Kramer, Priyakshi Kalita-De Croft, Sujeevi K Nawaratna, Manuel A Fernandez-Rojo, Geoffrey N Gobert, Janina E E Tirnitz-Parker, John K Olynyk, Ross W Shepherd, Peter J Lewindon, Grant A Ramm
Cystic fibrosis liver disease (CFLD) in children causes progressive fibrosis leading to biliary cirrhosis; however, its cause(s) and early pathogenesis are unclear. We hypothesized that a bile acid-induced ductular reaction (DR) drives fibrogenesis. The DR was evaluated by cytokeratin-7 immunohistochemistry in liver biopsies, staged for fibrosis, from 60 children with CFLD, and it demonstrated that the DR was significantly correlated with hepatic fibrosis stage and biliary taurocholate levels. To examine the mechanisms involved in DR induction, liver progenitor cells (LPCs) were treated with taurocholate, and key events in DR evolution were assessed: LPC proliferation, LPC biliary differentiation, and hepatic stellate cell (HSC) chemotaxis...
September 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28919113/hepatic-tmem30a-deficiency-causes-intrahepatic-cholestasis-by-impairing-expression-and-localization-of-bile-salt-transporters
#14
Leiming Liu, Lingling Zhang, Lin Zhang, Fan Yang, Xudong Zhu, Zhongjie Lu, Yeming Yang, Haiqi Lu, Lifeng Feng, Zhuo Wang, Hui Chen, Sheng Yan, Lin Wang, Zhenyu Ju, Hongchuan Jin, Xianjun Zhu
Mutations in ATP8B1 or ATP11C (members of P4-type ATPases) cause progressive familial intrahepatic cholestasis type 1 in human or intrahepatic cholestasis in mice. Transmembrane protein 30A (TMEM30A), as a β-subunit, is essential for the function of P4-type ATPases, including ATP8B1 and ATP11C; however, its role in the cause of cholestasis remains poorly understood. To investigate the function of TMEM30A in bile salt (BS) homeostasis, we developed Tmem30a liver-specific knockout (LKO) mice. Tmem30a LKO mice experienced hyperbilirubinemia, hypercholanemia, inflammatory infiltration, ductular proliferation, and liver fibrosis...
September 15, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28916805/an-hdac3-prox1-corepressor-module-acts-on-hnf4%C3%AE-to-control-hepatic-triglycerides
#15
Sean M Armour, Jarrett R Remsberg, Manashree Damle, Simone Sidoli, Wesley Y Ho, Zhenghui Li, Benjamin A Garcia, Mitchell A Lazar
The histone deacetylase HDAC3 is a critical mediator of hepatic lipid metabolism, and liver-specific deletion of HDAC3 leads to fatty liver. To elucidate the underlying mechanism, here we report a method of cross-linking followed by mass spectrometry to define a high-confidence HDAC3 interactome in vivo that includes the canonical NCoR-HDAC3 complex as well as Prospero-related homeobox 1 protein (PROX1). HDAC3 and PROX1 co-localize extensively on the mouse liver genome, and are co-recruited by hepatocyte nuclear factor 4α (HNF4α)...
September 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28912067/farnesoid-x-receptor-regulates-sult1e1-expression-through-inhibition-of-pgc1%C3%AE-binding-to-hnf4%C3%AE
#16
Shuai Wang, Xue Yuan, Danyi Lu, Lianxia Guo, Baojian Wu
Sulfotransferase 1E1 (SULT1E1, also known as estrogen sulfotransferase) plays an important role in metabolism and detoxification of many endogenous and exogenous compounds (e.g., estrogens and flavonoids). Here we aimed to assess the effects of farnesoid X receptor (FXR) activation on SULT1E1 expression, and to determine the mechanism thereof. Treatment with specific FXR agonists (i.e., GW4064 and CDCA) significantly decreased both mRNA and protein levels of SULT1E1 in HepG2 cells. This was accompanied by a decrease in the enzymatic activity...
September 11, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28882825/hepatocyte-nuclear-factor-4%C3%AE-regulates-the-expression-of-intestinal-epithelial-na-h-exchanger-isoform-3-nhe3
#17
Saminathan Muthusamy, Jong Jin Jeong, Ming Cheng, Jessica A Bonzo, Anoop Kumar, Frank J Gonzalez, Alip Borthakur, Pradeep K Dudeja, Seema Saksena, Jaleh Malakooti
The Na(+)/H(+) exchanger isoform-3 plays a key role in coupled electroneutral NaCl absorption in the mammalian intestine. Reduced NHE3 expression or function has been implicated in the pathogenesis of diarrhea associated with IBD or enteric infections. Our previous studies revealed transcriptional regulation of NHE3 by various agents such as TNF-, IFN-γ and butyrate involving the transcription factors SP1 and SP3. In silico analysis revealed that the NHE3 core promoter also contains a hepatocyte nuclear factor 4α (HNF4α) binding site that is evolutionarily conserved in several species suggesting that HNF4α has a role in NHE3 regulation...
September 7, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/28877455/global-analysis-of-plasma-lipids-identifies-liver-derived-acylcarnitines-as-a-fuel-source-for-brown-fat-thermogenesis
#18
Judith Simcox, Gisela Geoghegan, John Alan Maschek, Claire L Bensard, Marzia Pasquali, Ren Miao, Sanghoon Lee, Lei Jiang, Ian Huck, Erin E Kershaw, Anthony J Donato, Udayan Apte, Nicola Longo, Jared Rutter, Renate Schreiber, Rudolf Zechner, James Cox, Claudio J Villanueva
Cold-induced thermogenesis is an energy-demanding process that protects endotherms against a reduction in ambient temperature. Using non-targeted liquid chromatography-mass spectrometry-based lipidomics, we identified elevated levels of plasma acylcarnitines in response to the cold. We found that the liver undergoes a metabolic switch to provide fuel for brown fat thermogenesis by producing acylcarnitines. Cold stimulates white adipocytes to release free fatty acids that activate the nuclear receptor HNF4α, which is required for acylcarnitine production in the liver and adaptive thermogenesis...
September 5, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28870599/hepatocyte-nuclear-factor-4a-improves-hepatic-differentiation-of-immortalized-adult-human-hepatocytes-and-improves-liver-function-and-survival
#19
Hua-Lian Hang, Xin-Yu Liu, Hai-Tian Wang, Ning Xu, Jian-Min Bian, Jian-Jun Zhang, Lei Xia, Qiang Xia
Immortalized human hepatocytes (IHH) could provide an unlimited supply of hepatocytes, but insufficient differentiation and phenotypic instability restrict their clinical application. This study aimed to determine the role of hepatocyte nuclear factor 4A (HNF4A) in hepatic differentiation of IHH, and whether encapsulation of IHH overexpressing HNF4A could improve liver function and survival in rats with acute liver failure (ALF). Primary human hepatocytes were transduced with lentivirus-mediated catalytic subunit of human telomerase reverse transcriptase (hTERT) to establish IHH...
November 15, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28837897/effects-of-abcb1-abcc2-ugt2b7-and-hnf4%C3%AE-genetic-polymorphisms-on-oxcarbazepine-concentrations-and-therapeutic-efficacy-in-patients-with-epilepsy
#20
Chunhong Shen, Bijun Zhang, Zhirong Liu, Yelei Tang, Yinxi Zhang, Shan Wang, Yi Guo, Yao Ding, Shuang Wang, Meiping Ding
PURPOSE: The aim of the study is to investigate the effects of ABCB1, ABCC2, UGT2B7 and HNF4α genetic polymorphisms on plasma oxcarbazepine (OXC) concentrations and therapeutic efficacy in Han Chinese patients with epilepsy. METHODS: We recruited 116 Han Chinese patients with epilepsy who were receiving OXC monotherapy. Blood samples were taken and OXC levels were measured. The polymorphisms of ABCB1 rs1045642, ABCC2 rs2273697, UGT2B7 rs7439366, and HNF4α rs2071197 were determined...
October 2017: Seizure: the Journal of the British Epilepsy Association
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