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Wasco Wruck, James Adjaye
Induced pluripotent stem cells (iPSCs) and human embryonic stem cells (hESCs) differentiated into hepatocyte-like cells (HLCs) provide a defined and renewable source of cells for drug screening, toxicology and regenerative medicine. We previously reprogrammed human fetal foreskin fibroblast cells (HFF1) into iPSCs employing an episomal plasmid-based integration-free approach, this iPSC-line and the hESC lines H1 and H9 were used to model hepatogenesis in vitro. Biochemical characterisation confirmed glycogen storage, ICG uptake and release, urea and bile acid production, as well as CYP3A4 activity...
March 13, 2018: Scientific Data
Hong Wang, Guoxiu Cao, Guangji Wang, Haiping Hao
UDP-glucuronosyltransferases (UGTs) are a class of important phase II drug metabolizing enzymes (DMEs), playing essential roles in the homeostasis of endobiotics as well as the dispositional behavior of exogenous compounds. The expression and enzyme activity of UGTs are regulated by multiple dimensions of mechanisms and can be influenced by diverse factors. Thus, the intensive research of its regulatory network is pivotal for better understanding about the physiological, pathological, and therapeutic significance of UGTs...
March 7, 2018: Current Drug Metabolism
Nurul Mubarokah, Julie-Ann Hulin, Peter Ian Mackenzie, Ross A McKinnon, Alex Z Haines, Dong Gui Hu, Robyn Meech
The UDP-glucuronosyltransferases (UGTs) of the gastrointestinal tract (GIT) have a crucial role in protection against dietary toxins and metabolism of orally administered drugs. A subset of UGTs including UGT1A8, UGT1A9, and UGT1A10 are highly expressed in GI tissues and this has been shown to be at least partly directed by the caudal homeodomain transcription factor, CDX2. We sought to further define the factors involved in regulation of the UGT1A8-1A10 genes and identified a novel composite element located within the proximal promoters of these three genes that binds to both CDX2 and the hepatocyte nuclear factor HNF4α, and mediates synergistic activation by these factors...
March 8, 2018: Molecular Pharmacology
Jessica Cusato, Amedeo De Nicolò, Lucio Boglione, Fabio Favata, Alessandra Ariaudo, Simone Mornese Pinna, Chiara Carcieri, Federica Guido, Valeria Avataneo, Giuseppe Cariti, Giovanni Di Perri, Antonio D'Avolio
Background: Sofosbuvir is a potent nucleotide HCV NS5B polymerase inhibitor that is also a P-glycoprotein (encoded by the ABCB1 gene) and breast cancer resistance protein (encoded by the ABCG2 gene) substrate. Concerning previous anti-HCV therapies, pharmacogenetics had a significant impact, particularly considering the association of interleukin28B polymorphisms with dual-therapy (ribavirin + pegylated IFN) outcomes. Objectives: In this work, we investigated the association between sofosbuvir and its prevalent metabolite (GS-331007) plasma concentrations at 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCG2 and HNF4α) related to sofosbuvir transport...
March 2, 2018: Journal of Antimicrobial Chemotherapy
Eduardo H Gilglioni, Jung-Chin Chang, Suzanne Duijst, Simei Go, Aziza A A Adam, Ruurdtje Hoekstra, Arthur J Verhoeven, Emy L Ishii-Iwamoto, Ronald P J Oude Elferink
Primary hepatocyte culture is an important in vitro system for the study of liver functions. In vivo , hepatocytes have high oxidative metabolism. However, oxygen supply by means of diffusion in in vitro static cultures is much less than that by blood circulation in vivo . Therefore, we investigated whether hypoxia contributes to dedifferentiation and deregulated metabolism in cultured hepatocytes. To this end, murine hepatocytes were cultured under static or shaken (60 revolutions per minute) conditions in a collagen sandwich...
March 2018: Hepatology Communications
Naoki Nakajima, Akihiko Yoshizawa, Tomoyuki Nakajima, Masahiro Hirata, Ayako Furuhata, Shinji Sumiyoshi, Mariyo Rokutan-Kurata, Makoto Sonobe, Toshi Menju, Ei Miyamoto, Toyofumi F Chen-Yoshikawa, Hiroshi Date, Hironori Haga
AIMS: GATA6 is known to play a role in lung development. However, its role in the carcinogenesis of lung cancer is not well studied. The aim of this study was to analyze GATA6 expression in lung adenocarcinomas (LA) by immunohistochemistry (IHC) to define its association with clinicopathological characteristics. METHODS AND RESULTS: IHC analysis of GATA6 was performed using tissue microarray slides containing 348 LAs. The association between GATA6 expression and clinicopathological parameters was evaluated...
February 22, 2018: Histopathology
Jung Eun Park, Mikang Lee, Seong-Chul Kim, Yanqiao Zhang, James P Hardwick, Yoon Kwang Lee
Peroxisome proliferator-activated receptor gamma (PPARγ) is a master regulator for white adipocyte differentiation and lipid storage. The increased level of hepatic PPARγ2 isoform reprograms liver for lipid storage and causes abnormal fat accumulation in certain pathophysiologic conditions. The current study aimed to investigate a role of transcriptional repressor hairy and enhancer of split 6 (HES6) in the regulation of Pparg2 expression and hepatic steatosis induced by diet. Liver-specific overexpression of Hes6 using adenovirus reduced Pparg2 messenger RNA levels by 90% and hepatic triglyceride accumulation by 22% compared to the levels in mice injected with an adenoviral empty vector with Western diet feeding...
December 2017: Hepatology Communications
Yuhan Bi, Xiongjie Shi, Junjie Zhu, Xiudong Guan, Wojciech G Garbacz, Yixian Huang, Li Gao, Jiong Yan, Meishu Xu, Songrong Ren, Shunlin Ren, Yulan Liu, Xiaochao Ma, Song Li, Wen Xie
The cholesterol sulfotransferase SULT2B1b converses cholesterol to cholesterol sulfate (CS). We previously reported that SULT2B1b inhibits hepatic gluconeogenesis by antagonizing the gluconeogenic activity of hepatocyte nuclear factor 4α (HNF4α). In this study, we showed that the SULT2B1b gene is a transcriptional target of HNF4α, which led to our hypothesis that the induction of SULT2B1b by HNF4α represents a negative feedback to limit the gluconeogenic activity of HNF4α. Indeed, down-regulation of Sult2B1b enhanced the gluconeogenic activity of HNF4α, which may have been accounted for by the increased acetylation of HNF4α as a result of decreased expression of the HNF4α deacetylase Sirt1...
January 29, 2018: Molecular and Cellular Biology
Shuqi Wang, Junliang Chen, Danli Jiang, Qinghao Zhang, Cuihong You, Douglas R Tocher, Óscar Monroig, Yewei Dong, Yuanyou Li
Long-chain polyunsaturated fatty acid (LC-PUFA) biosynthesis is an important metabolic pathway in vertebrates, especially fish, considering they are the major source of n-3 LC-PUFA in the human diet. However, most fish have only limited capability for biosynthesis of LC-PUFA. The rabbitfish (Siganus canaliculatus) is able to synthesize LC-PUFA as it has all the key enzyme activities required including Δ6Δ5 Fads2, Δ4 Fads2, Elovl5, and Elovl4. We previously reported a direct interaction between the transcription factor Hnf4α and the promoter regions of Δ4 and Δ6Δ5 Fads2, which suggested that Hnf4α was involved in the transcriptional regulation of fads2 in rabbitfish...
January 19, 2018: Fish Physiology and Biochemistry
Xi Yang, Yinjia Fu, Fuqing Hu, Xuelai Luo, Junbo Hu, Guihua Wang
Phosphatidylinositol 3-kinase (PI3K) signaling plays an important role in the regulation of cellular lipid metabolism and non-alcoholic fatty liver disease (NAFLD). However, little is known about the role of the regulatory subunits of PI3K in lipid metabolism and NAFLD. In this study, we characterized the functional role of PIK3R3 in fasting-induced hepatic lipid metabolism. In this study, we showed that the overexpression of PIK3R3 promoted hepatic fatty acid oxidation via PIK3R3-induced expression of PPARα, thus improving the fatty liver phenotype in high-fat diet (HFD)-induced mice...
January 19, 2018: Experimental & Molecular Medicine
Shangdong Guo, Hong Lu
Hepatocyte nuclear factor 4-alpha (HNF4α) is a well-established master regulator of liver development and function. Restoration of HNF4α can treat multiple liver disorders and liver cancers. To date, HNF4α is still "undruggable" due to lack of known activating ligands. Thus, understanding the regulatory mechanism of HNF4α expression may help develop an alternative approach to modulate HNF4α protein levels. G-quadruplexes (G4) are non-canonical stable secondary structures discovered mostly in the promoters of oncogenes...
January 13, 2018: Molecular and Cellular Biochemistry
Elzbieta Sucajtys-Szulc, Alicja Debska-Slizien, Boleslaw Rutkowski, Ryszard Milczarek, Iwona Pelikant-Malecka, Tomasz Sledzinski, Julian Swierczynski, Marek Szolkiewicz
Inflammation related to chronic kidney disease (CKD) is an important clinical problem. We recently determined that hepatocyte nuclear factor 1α (HNF1α) was upregulated in the livers of chronic renal failure (CRF) rats-experimental model of CKD. Considering that the promoter region of gene encoding C-reactive protein (CRP) contains binding sites for HNF1α and that the loss-of-function mutation in the Hnfs1α leads to significant reduction in circulating CRP levels, we hypothesized that HNF1α can activate the Crp in CRF rats...
January 12, 2018: Molecular and Cellular Biochemistry
Yewei Dong, Jianhong Zhao, Junliang Chen, Shuqi Wang, Yang Liu, Qinghao Zhang, Cuihong You, Óscar Monroig, Douglas R Tocher, Yuanyou Li
The rabbitfish Siganus canaliculatus was the first marine teleost demonstrated to have the ability of biosynthesizing long-chain polyunsaturated fatty acids (LC-PUFA) from C18 PUFA precursors, and all genes encoding the key enzymes for LC-PUFA biosynthesis have been cloned and functionally characterized, which provides us a potential model to study the regulatory mechanisms of LC-PUFA biosynthesis in teleosts. As the primary step to clarify such mechanisms, present research focused on promoter analysis of gene encoding ∆6/∆5 fatty acyl desaturase (Fad), a rate-limiting enzyme catalyzing the first step in the conversion of C18 PUFA to LC-PUFA...
January 9, 2018: Gene
Amrita Palaria, Jesse R Angelo, Taylor Guertin, Jesse Mager, Kimberly D Tremblay
During development, the endoderm initiates organ-restricted gene expression patterns in a spatiotemporally controlled manner. This process, termed induction, requires signals from adjacent mesodermal derivatives. Fibroblast Growth Factor (FGF) and Bone Morphogenetic Protein (BMP) emanating from the cardiac mesoderm and the septum transversum mesenchyme (STM), respectively, are believed to be simultaneously and uniformly required to directly induce hepatic gene expression from the murine endoderm. Using small molecule inhibitors of BMP signals during liver bud induction in the developing mouse embryo, we find that BMP signaling is not uniformly required to induce hepatic gene expression...
January 5, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Shangdong Guo, Hong Lu
Hepatocyte nuclear factor 4-alpha (HNF4α) is a well established master regulator of liver development and function. We identified the in vitro presence of a stable secondary structure, G-quadruplex (G4) in the 5' UTR of P1-HNF4A, the predominant HNF4α isoform(s) in adult liver. Our data suggest that the cooperation of G4 and the adjacent putative protein-binding sites within the 5' UTR was necessary and sufficient to mediate a strong translational repression. This was supported by analysis of deleted/mutated 5'UTRs and two native regulatory single-nucleotide polymorphisms in the 5'UTR...
December 12, 2017: Scientific Reports
Jie Deng, Martin Mueller, Tingting Geng, Yuanyuan Shen, Ya Liu, Peng Hou, Ramanaiah Ramillapalli, Hugh S Taylor, Michael Paidas, Yingqun Huang
Metformin is the most widely used anti-diabetic medication worldwide. However, human and animal studies suggest that prenatal metformin exposure may increase the risk of metabolic disorders in adult offspring, yet the underpinning mechanism remains unclear. Here we report that metformin-exposed mouse fetuses exhibit elevated expression of the H19 long noncoding RNA, which induces hypomethylation and increased expression of hepatocyte nuclear factor 4α (HNF4α). As a transcription factor essential for morphological and functional differentiation of hepatocytes, HNF4α also has an indispensable role in the regulation of expression of gluconeogenic genes...
December 7, 2017: Cell Death & Disease
Hwee Hui Lau, Natasha Hui Jin Ng, Larry Sai Weng Loo, Joanita Binte Jasmen, Adrian Kee Keong Teo
The hepatocyte nuclear factors (HNFs) namely HNF1α/β, FOXA1/2/3, HNF4α/γ and ONECUT1/2 are expressed in a variety of tissues and organs, including the liver, pancreas and kidney. The spatial and temporal manner of HNF expression regulates embryonic development and subsequently the development of multiple tissues during adulthood. Though the HNFs were initially identified individually based on their roles in the liver, numerous studies have now revealed that the HNFs cross-regulate one another and exhibit synergistic relationships in the regulation of tissue development and function...
November 24, 2017: Journal of Hepatology
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
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
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
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