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1.
Front Endocrinol (Lausanne) ; 14: 1266527, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38111711

RESUMO

Hepatocyte Nuclear Factor 4α (HNF4α), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2) which drive the expression of different isoforms. P1-HNF4α is the major isoform in the adult liver while P2-HNF4α is thought to be expressed only in fetal liver and liver cancer. Here, we show that P2-HNF4α is indeed expressed in the normal adult liver at Zeitgeber time (ZT)9 and ZT21. Using exon swap mice that express only P2-HNF4α we show that this isoform orchestrates a distinct transcriptome and metabolome via unique chromatin and protein-protein interactions, including with different clock proteins at different times of the day leading to subtle differences in circadian gene regulation. Furthermore, deletion of the Clock gene alters the circadian oscillation of P2- (but not P1-)HNF4α RNA, revealing a complex feedback loop between the HNF4α isoforms and the hepatic clock. Finally, we demonstrate that while P1-HNF4α drives gluconeogenesis, P2-HNF4α drives ketogenesis and is required for elevated levels of ketone bodies in female mice. Taken together, we propose that the highly conserved two-promoter structure of the Hnf4a gene is an evolutionarily conserved mechanism to maintain the balance between gluconeogenesis and ketogenesis in the liver in a circadian fashion.


Assuntos
Fator 4 Nuclear de Hepatócito , Metabolismo dos Lipídeos , Animais , Feminino , Camundongos , Carboidratos , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
2.
Sci Rep ; 13(1): 22758, 2023 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-38151490

RESUMO

High fat diets (HFDs) have been linked to several diseases including obesity, diabetes, fatty liver, inflammatory bowel disease (IBD) and colon cancer. In this study, we examined the impact on intestinal gene expression of three isocaloric HFDs that differed only in their fatty acid composition-coconut oil (saturated fats), conventional soybean oil (polyunsaturated fats) and a genetically modified soybean oil (monounsaturated fats). Four functionally distinct segments of the mouse intestinal tract were analyzed using RNA-seq-duodenum, jejunum, terminal ileum and proximal colon. We found considerable dysregulation of genes in multiple tissues with the different diets, including those encoding nuclear receptors and genes involved in xenobiotic and drug metabolism, epithelial barrier function, IBD and colon cancer as well as genes associated with the microbiome and COVID-19. Network analysis shows that genes involved in metabolism tend to be upregulated by the HFDs while genes related to the immune system are downregulated; neurotransmitter signaling was also dysregulated by the HFDs. Genomic sequencing also revealed a microbiome altered by the HFDs. This study highlights the potential impact of different HFDs on gut health with implications for the organism as a whole and will serve as a reference for gene expression along the length of the intestines.


Assuntos
Neoplasias do Colo , Doenças Inflamatórias Intestinais , Microbiota , Animais , Camundongos , Dieta Hiperlipídica/efeitos adversos , Óleo de Soja , Gorduras na Dieta/farmacologia , Gorduras na Dieta/metabolismo , Ácidos Graxos , Íleo/metabolismo , Expressão Gênica
3.
Res Sq ; 2023 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-37886485

RESUMO

High fat diets (HFDs) have been linked to several diseases including obesity, diabetes, fatty liver, inflammatory bowel disease (IBD) and colon cancer. In this study, we examined the impact on intestinal gene expression of three isocaloric HFDs that differed only in their fatty acid composition - coconut oil (saturated fats), conventional soybean oil (polyunsaturated fats) and a genetically modified soybean oil (monounsaturated fats). Four functionally distinct segments of the mouse intestinal tract were analyzed using RNA-seq - duodenum, jejunum, terminal ileum and proximal colon. We found considerable dysregulation of genes in multiple tissues with the different diets, including those encoding nuclear receptors and genes involved in xenobiotic and drug metabolism, epithelial barrier function, IBD and colon cancer as well as genes associated with the microbiome and COVID-19. Network analysis shows that genes involved in metabolism tend to be upregulated by the HFDs while genes related to the immune system are downregulated; neurotransmitter signaling was also dysregulated by the HFDs. Genomic sequencing also revealed a microbiome altered by the HFDs. This study highlights the potential impact of different HFDs on gut health with implications for the organism as a whole and will serve as a reference for gene expression along the length of the intestines.

4.
Endocrinology ; 161(2)2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31912136

RESUMO

Soybean oil consumption has increased greatly in the past half-century and is linked to obesity and diabetes. To test the hypothesis that soybean oil diet alters hypothalamic gene expression in conjunction with metabolic phenotype, we performed RNA sequencing analysis using male mice fed isocaloric, high-fat diets based on conventional soybean oil (high in linoleic acid, LA), a genetically modified, low-LA soybean oil (Plenish), and coconut oil (high in saturated fat, containing no LA). The 2 soybean oil diets had similar but nonidentical effects on the hypothalamic transcriptome, whereas the coconut oil diet had a negligible effect compared to a low-fat control diet. Dysregulated genes were associated with inflammation, neuroendocrine, neurochemical, and insulin signaling. Oxt was the only gene with metabolic, inflammation, and neurological relevance upregulated by both soybean oil diets compared to both control diets. Oxytocin immunoreactivity in the supraoptic and paraventricular nuclei of the hypothalamus was reduced, whereas plasma oxytocin and hypothalamic Oxt were increased. These central and peripheral effects of soybean oil diets were correlated with glucose intolerance but not body weight. Alterations in hypothalamic Oxt and plasma oxytocin were not observed in the coconut oil diet enriched in stigmasterol, a phytosterol found in soybean oil. We postulate that neither stigmasterol nor LA is responsible for effects of soybean oil diets on oxytocin and that Oxt messenger RNA levels could be associated with the diabetic state. Given the ubiquitous presence of soybean oil in the American diet, its observed effects on hypothalamic gene expression could have important public health ramifications.


Assuntos
Diabetes Mellitus/etiologia , Expressão Gênica/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Ocitocina/sangue , Óleo de Soja/efeitos adversos , Animais , Inflamação/etiologia , Ácido Linoleico/efeitos adversos , Masculino , Camundongos , Doenças do Sistema Nervoso/etiologia , Obesidade/etiologia , Estigmasterol/efeitos adversos
5.
Nat Commun ; 9(1): 4349, 2018 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-30341289

RESUMO

Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of liver-specific gene expression with potent tumor suppressor activity, yet many liver tumors express HNF4α. This study reveals that P1-HNF4α, the predominant isoform expressed in the adult liver, inhibits expression of tumor promoting genes in a circadian manner. In contrast, an additional isoform of HNF4α, driven by an alternative promoter (P2-HNF4α), is induced in HNF4α-positive human hepatocellular carcinoma (HCC). P2-HNF4α represses the circadian clock gene ARNTL (BMAL1), which is robustly expressed in healthy hepatocytes, and causes nuclear to cytoplasmic re-localization of P1-HNF4α. We reveal mechanisms underlying the incompatibility of BMAL1 and P2-HNF4α in HCC, and demonstrate that forced expression of BMAL1 in HNF4α-positive HCC prevents the growth of tumors in vivo. These data suggest that manipulation of the circadian clock in HNF4α-positive HCC could be a tractable strategy to inhibit tumor growth and progression in the liver.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Carcinoma Hepatocelular/metabolismo , Fator 4 Nuclear de Hepatócito/fisiologia , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição ARNTL/genética , Transporte Ativo do Núcleo Celular , Carcinoma Hepatocelular/patologia , Relógios Circadianos , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Hepatócitos/metabolismo , Neoplasias Hepáticas/patologia , Isoformas de Proteínas/fisiologia
6.
Mol Cell Biol ; 35(20): 3471-90, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26240283

RESUMO

The nuclear receptor hepatocyte nuclear factor 4α (HNF4α) is tumor suppressive in the liver but amplified in colon cancer, suggesting that it also might be oncogenic. To investigate whether this discrepancy is due to different HNF4α isoforms derived from its two promoters (P1 and P2), we generated Tet-On-inducible human colon cancer (HCT116) cell lines that express either the P1-driven (HNF4α2) or P2-driven (HNF4α8) isoform and analyzed them for tumor growth and global changes in gene expression (transcriptome sequencing [RNA-seq] and chromatin immunoprecipitation sequencing [ChIP-seq]). The results show that while HNF4α2 acts as a tumor suppressor in the HCT116 tumor xenograft model, HNF4α8 does not. Each isoform regulates the expression of distinct sets of genes and recruits, colocalizes, and competes in a distinct fashion with the Wnt/ß-catenin mediator T-cell factor 4 (TCF4) at CTTTG motifs as well as at AP-1 motifs (TGAXTCA). Protein binding microarrays (PBMs) show that HNF4α and TCF4 share some but not all binding motifs and that single nucleotide polymorphisms (SNPs) in sites bound by both HNF4α and TCF4 can alter binding affinity in vitro, suggesting that they could play a role in cancer susceptibility in vivo. Thus, the HNF4α isoforms play distinct roles in colon cancer, which could be due to differential interactions with the Wnt/ß-catenin/TCF4 and AP-1 pathways.


Assuntos
Neoplasias Colorretais/metabolismo , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 4 Nuclear de Hepatócito/fisiologia , Fator de Transcrição AP-1/metabolismo , Animais , Sequência de Bases , Ligação Competitiva , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Sequência Consenso , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Células HCT116 , Humanos , Masculino , Camundongos Nus , Transplante de Neoplasias , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Isoformas de Proteínas/fisiologia , Transcriptoma , Carga Tumoral
7.
RNA ; 13(11): 1923-39, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17901154

RESUMO

As the genomes of more eukaryotic pathogens are sequenced, understanding how molecular differences between parasite and host might be exploited to provide new therapies has become a major focus. Central to cell function are RNA-containing complexes involved in gene expression, such as the ribosome, the spliceosome, snoRNAs, RNase P, and telomerase, among others. In this article we identify by comparative genomics and validate by RNA analysis numerous previously unknown structural RNAs encoded by the Plasmodium falciparum genome, including the telomerase RNA, U3, 31 snoRNAs, as well as previously predicted spliceosomal snRNAs, SRP RNA, MRP RNA, and RNAse P RNA. Furthermore, we identify six new RNA coding genes of unknown function. To investigate the relationships of the RNA coding genes to other genomic features in related parasites, we developed a genome browser for P. falciparum (http://areslab.ucsc.edu/cgi-bin/hgGateway). Additional experiments provide evidence supporting the prediction that snoRNAs guide methylation of a specific position on U4 snRNA, as well as predicting an snRNA promoter element particular to Plasmodium sp. These findings should allow detailed structural comparisons between the RNA components of the gene expression machinery of the parasite and its vertebrate hosts.


Assuntos
Genoma de Protozoário , Genômica , Plasmodium falciparum/genética , RNA de Protozoário/química , Animais , Pareamento de Bases , Sequência de Bases , Humanos , Malária/parasitologia , Metilação , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Plasmodium falciparum/metabolismo , RNA/química , RNA/metabolismo , RNA Ribossômico/química , RNA Ribossômico/metabolismo , RNA Nuclear Pequeno/química , RNA Nucleolar Pequeno/química , RNA Nucleolar Pequeno/metabolismo , RNA de Transferência/química , RNA de Transferência/metabolismo , Spliceossomos , Telomerase/química , Telomerase/metabolismo
8.
J Laryngol Otol ; 118(4): 305-6, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15117472

RESUMO

A rare case of nasal polyposis requiring urgent tracheostomy is reported. A 70-year-old male presented to the hospital with stridor. He had a 10-year history of nasal obstruction. A large proliferative mass was found to be occupying both the nasal cavities. An emergency tracheostomy and biopsy of the lesion was performed. A computerized axial scan (CT) demonstrated that the lesion occupied the pharynx reaching up to the laryngeal inlet. To our knowledge this is the first case reported in the literature. Upper airway obstruction from nasal polyps is uncommon but can cause significant morbidity if not appropriately managed.


Assuntos
Obstrução das Vias Respiratórias/etiologia , Obstrução das Vias Respiratórias/cirurgia , Pólipos Nasais/complicações , Traqueostomia , Idoso , Emergências , Humanos , Masculino , Pólipos Nasais/diagnóstico por imagem , Tomografia Computadorizada por Raios X
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