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https://www.readbyqxmd.com/read/26684275/increased-bile-acid-synthesis-and-impaired-bile-acid-transport-in-human-obesity
#1
Rebecca A Haeusler, Stefania Camastra, Monica Nannipieri, Brenno Astiarraga, Jose Castro-Perez, Dan Xie, Liangsu Wang, Manu Chakravarthy, Ele Ferrannini
CONTEXT: Alterations in bile acid (BA) synthesis and transport have the potential to affect multiple metabolic pathways in the pathophysiology of obesity. OBJECTIVE: The objective of the study was to investigate the effects of obesity on serum fluctuations of BAs and markers of BA synthesis. DESIGN: We measured BA fluctuations in 11 nonobese and 32 obese subjects and BA transporter expression in liver specimens from 42 individuals and specimens of duodenum, jejunum, ileum, colon, and pancreas from nine individuals...
May 2016: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/26015549/increased-bile-acid-synthesis-and-deconjugation-after-biliopancreatic-diversion
#2
COMPARATIVE STUDY
Ele Ferrannini, Stefania Camastra, Brenno Astiarraga, Monica Nannipieri, Jose Castro-Perez, Dan Xie, Liangsu Wang, Manu Chakravarthy, Rebecca A Haeusler
Biliopancreatic diversion (BPD) improves insulin sensitivity and decreases serum cholesterol out of proportion with weight loss. Mechanisms of these effects are unknown. One set of proposed contributors to metabolic improvements after bariatric surgeries is bile acids (BAs). We investigated the early and late effects of BPD on plasma BA levels, composition, and markers of BA synthesis in 15 patients with type 2 diabetes (T2D). We compared these to the early and late effects of Roux-en-Y gastric bypass (RYGB) in 22 patients with T2D and 16 with normal glucose tolerance...
October 2015: Diabetes
https://www.readbyqxmd.com/read/25737948/decreased-expression-of-hepatic-glucokinase-in-type-2-diabetes
#3
Rebecca A Haeusler, Stefania Camastra, Brenno Astiarraga, Monica Nannipieri, Marco Anselmino, Ele Ferrannini
BACKGROUND/OBJECTIVES: Increased endogenous glucose production is a hallmark of type 2 diabetes. Evidence from animal models has suggested that a likely cause of this is increased mRNA expression of glucose 6-phosphatase and phosphoenolpyruvate carboxykinase (encoded by G6PC, PCK1 and PCK2). But another contributing factor may be decreased liver glucokinase (encoded by GCK). METHODS: We examined expression of these enzymes in liver biopsies from 12 nondiabetic and 28 diabetic individuals...
March 2015: Molecular Metabolism
https://www.readbyqxmd.com/read/25307742/integrated-control-of-hepatic-lipogenesis-versus-glucose-production-requires-foxo-transcription-factors
#4
Rebecca A Haeusler, Kirsten Hartil, Bhavapriya Vaitheesvaran, Isabel Arrieta-Cruz, Colette M Knight, Joshua R Cook, Helene L Kammoun, Mark A Febbraio, Roger Gutierrez-Juarez, Irwin J Kurland, Domenico Accili
Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model of insulin signalling, with FoxO1 presiding over glucose production and Srebp-1c regulating lipogenesis, provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO...
October 13, 2014: Nature Communications
https://www.readbyqxmd.com/read/23898186/mod5-protein-binds-to-trna-gene-complexes-and-affects-local-transcriptional-silencing
#5
Matthew Pratt-Hyatt, Dave A Pai, Rebecca A Haeusler, Glenn G Wozniak, Paul D Good, Erin L Miller, Ian X McLeod, John R Yates, Anita K Hopper, David R Engelke
The tRNA gene-mediated (tgm) silencing of RNA polymerase II promoters is dependent on subnuclear clustering of the tRNA genes, but genetic analysis shows that the silencing requires additional mechanisms. We have identified proteins that bind tRNA gene transcription complexes and are required for tgm silencing but not required for gene clustering. One of the proteins, Mod5, is a tRNA modifying enzyme that adds an N6-isopentenyl adenosine modification at position 37 on a small number of tRNAs in the cytoplasm, although a subpopulation of Mod5 is also found in the nucleus...
August 13, 2013: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/23884887/human-insulin-resistance-is-associated-with-increased-plasma-levels-of-12%C3%AE-hydroxylated-bile-acids
#6
Rebecca A Haeusler, Brenno Astiarraga, Stefania Camastra, Domenico Accili, Ele Ferrannini
Bile acids (BAs) exert pleiotropic metabolic effects, and physicochemical properties of different BAs affect their function. In rodents, insulin regulates BA composition, in part by regulating the BA 12α-hydroxylase CYP8B1. However, it is unclear whether a similar effect occurs in humans. To address this question, we examined the relationship between clamp-measured insulin sensitivity and plasma BA composition in a cohort of 200 healthy subjects and 35 type 2 diabetic (T2D) patients. In healthy subjects, insulin resistance (IR) was associated with increased 12α-hydroxylated BAs (cholic acid, deoxycholic acid, and their conjugated forms)...
December 2013: Diabetes
https://www.readbyqxmd.com/read/22426206/regulation-of-hepatic-ldl-receptors-by-mtorc1-and-pcsk9-in-mice
#7
Ding Ai, Chiyuan Chen, Seongah Han, Anjali Ganda, Andrew J Murphy, Rebecca Haeusler, Edward Thorp, Domenico Accili, Jay D Horton, Alan R Tall
Individuals with type 2 diabetes have an increased risk of atherosclerosis. One factor underlying this is dyslipidemia, which in hyperinsulinemic subjects with early type 2 diabetes is typically characterized by increased VLDL secretion but normal LDL cholesterol levels, possibly reflecting enhanced catabolism of LDL via hepatic LDLRs. Recent studies have also suggested that hepatic insulin signaling sustains LDLR levels. We therefore sought to elucidate the mechanisms linking hepatic insulin signaling to regulation of LDLR levels...
April 2012: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/22197325/impaired-generation-of-12-hydroxylated-bile-acids-links-hepatic-insulin-signaling-with-dyslipidemia
#8
Rebecca A Haeusler, Matthew Pratt-Hyatt, Carrie L Welch, Curtis D Klaassen, Domenico Accili
The association of type 2 diabetes with elevated plasma triglyceride (TG) and very low-density lipoproteins (VLDL), and intrahepatic lipid accumulation represents a pathophysiological enigma and an unmet therapeutic challenge. Here, we uncover a link between insulin action through FoxO1, bile acid (BA) composition, and altered lipid homeostasis that brings new insight to this longstanding conundrum. FoxO1 ablation brings about two signature lipid abnormalities of diabetes and the metabolic syndrome, elevated liver and plasma TG...
January 4, 2012: Cell Metabolism
https://www.readbyqxmd.com/read/22055502/dissociation-of-the-glucose-and-lipid-regulatory-functions-of-foxo1-by-targeted-knockin-of-acetylation-defective-alleles-in-mice
#9
Alexander S Banks, Ja Young Kim-Muller, Teresa L Mastracci, Natalie M Kofler, Li Qiang, Rebecca A Haeusler, Michael J Jurczak, Dina Laznik, Garrett Heinrich, Varman T Samuel, Gerald I Shulman, Virginia E Papaioannou, Domenico Accili
FoxO1 integrates multiple metabolic pathways. Nutrient levels modulate FoxO1 acetylation, but the functional consequences of this posttranslational modification are unclear. To answer this question, we generated mice bearing alleles that encode constitutively acetylated and acetylation-defective FoxO1 proteins. Homozygosity for an allele mimicking constitutive acetylation (Foxo1(KQ/KQ)) results in embryonic lethality due to cardiac and angiogenesis defects. In contrast, mice homozygous for a constitutively deacetylated Foxo1 allele (Foxo1(KR/KR)) display a unique metabolic phenotype of impaired insulin action on hepatic glucose metabolism but decreased plasma lipid levels and low respiratory quotient that are consistent with a state of preferential lipid usage...
November 2, 2011: Cell Metabolism
https://www.readbyqxmd.com/read/20880840/foxos-function-synergistically-to-promote-glucose-production
#10
Rebecca A Haeusler, Klaus H Kaestner, Domenico Accili
Hepatic glucose production (HGP) plays a vital role in maintaining the supply of glucose to the body, and transcription factor FoxO1 is known to confer hormone responsiveness onto HGP. Mice with a liver-specific FoxO1 deletion (L-FoxO1) show reduced HGP and reduced expression of glucose production genes. To determine the contribution of additional transcription factors to HGP, we created double and triple liver-specific knock-outs lacking FoxO1, FoxO3, and FoxO4 or the related protein FoxA2. We show that, when compared with single knock-out of FoxO1, triple ablation of FoxO genes causes more pronounced fasting hypoglycemia, increased glucose tolerance, and enhanced insulin sensitivity, with decreased plasma insulin levels...
November 12, 2010: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/20573950/hepatic-foxo1-ablation-exacerbates-lipid-abnormalities-during-hyperglycemia
#11
Rebecca A Haeusler, Seongah Han, Domenico Accili
Patients with diabetes suffer disproportionately from impaired lipid metabolism and cardiovascular disease, but the relevant roles of insulin resistance and hyperglycemia in these processes are unclear. Transcription factor FoxO1 is regulated dually by insulin and nutrients. In this study, we addressed the hypothesis that, in addition to its established role to regulate hepatic glucose production, FoxO1 controls aspects of lipid metabolism in the diabetic liver. Mice with a liver-specific deletion of FoxO1 (L-FoxO1) and their control littermates were rendered hyperglycemic by streptozotocin administration...
August 27, 2010: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/18708579/clustering-of-yeast-trna-genes-is-mediated-by-specific-association-of-condensin-with-trna-gene-transcription-complexes
#12
Rebecca A Haeusler, Matthew Pratt-Hyatt, Paul D Good, Theresa A Gipson, David R Engelke
The 274 tRNA genes in Saccharomyces cerevisiae are scattered throughout the linear maps of the 16 chromosomes, but the genes are clustered at the nucleolus when compacted in the nucleus. This clustering is dependent on intact nucleolar organization and contributes to tRNA gene-mediated (tgm) silencing of RNA polymerase II transcription near tRNA genes. After examination of the localization mechanism, we find that the chromosome-condensing complex, condensin, is involved in the clustering of tRNA genes. Conditionally defective mutations in all five subunits of condensin, which we confirm is bound to active tRNA genes in the yeast genome, lead to loss of both pol II transcriptional silencing near tRNA genes and nucleolar clustering of the genes...
August 15, 2008: Genes & Development
https://www.readbyqxmd.com/read/18590687/the-double-life-of-irs
#13
REVIEW
Rebecca A Haeusler, Domenico Accili
The liver plays a central role in lipid and glucose metabolism. Two studies in this issue (Kubota et al., 2008; Dong et al., 2008) on the insulin-signaling adaptors Irs1 and Irs2 prompt a critical reappraisal of the physiology of fasting and of the integrated control of hepatic insulin action.
July 2008: Cell Metabolism
https://www.readbyqxmd.com/read/17005718/protein-kinase-a-regulates-rna-polymerase-iii-transcription-through-the-nuclear-localization-of-maf1
#14
Robyn D Moir, JaeHoon Lee, Rebecca A Haeusler, Neelam Desai, David R Engelke, Ian M Willis
Maf1 is an essential and specific mediator of transcriptional repression in the RNA polymerase (pol) III system. Maf1-dependent repression occurs in response to a wide range of conditions, suggesting that the protein itself is targeted by the major nutritional and stress-signaling pathways. We show that Maf1 is a substrate for cAMP-dependent PKA in vitro and is differentially phosphorylated on PKA sites in vivo under normal versus repressing conditions. PKA activity negatively regulates Maf1 function because strains with unregulated high PKA activity block repression of pol III transcription in vivo, and strains lacking all PKA activity are hyperrepressible...
October 10, 2006: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/16971453/spatial-organization-of-transcription-by-rna-polymerase-iii
#15
REVIEW
Rebecca A Haeusler, David R Engelke
RNA polymerase III (pol III) transcribes many essential, small, noncoding RNAs, including the 5S rRNAs and tRNAs. While most pol III-transcribed genes are found scattered throughout the linear chromosome maps or in multiple linear clusters, there is increasing evidence that many of these genes prefer to be spatially clustered, often at or near the nucleolus. This association could create an environment that fosters the coregulation of transcription by pol III with transcription of the large ribosomal RNA repeats by RNA polymerase I (pol I) within the nucleolus...
2006: Nucleic Acids Research
https://www.readbyqxmd.com/read/15654076/silencing-near-trna-genes-requires-nucleolar-localization
#16
Li Wang, Rebecca A Haeusler, Paul D Good, Martin Thompson, Sapna Nagar, David R Engelke
Transcription by RNA polymerase II is antagonized by the presence of a nearby tRNA gene in Saccharomyces cerevisiae. To test hypotheses concerning the mechanism of this tRNA gene-mediated (tgm) silencing, the effects of specific gene deletions were determined. The results show that the mechanism of silencing near tRNA genes is fundamentally different from other forms of transcriptional silencing in yeast. Rather, tgm silencing is dependent on the ability to cluster the dispersed tRNA genes in or near the nucleolus, constituting a form of three-dimensional gene control...
March 11, 2005: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/15173119/dna-mapping-using-microfluidic-stretching-and-single-molecule-detection-of-fluorescent-site-specific-tags
#17
Eugene Y Chan, Nuno M Goncalves, Rebecca A Haeusler, Amie J Hatch, Jonathan W Larson, Anthony M Maletta, Gregory R Yantz, Eugene D Carstea, Martin Fuchs, Gordon G Wong, Steven R Gullans, Rudolf Gilmanshin
We have developed a rapid molecular mapping technology--Direct Linear Analysis (DLA)--on the basis of the analysis of individual DNA molecules bound with sequence-specific fluorescent tags. The apparatus includes a microfluidic device for stretching DNA molecules in elongational flow that is coupled to a multicolor detection system capable of single-fluorophore sensitivity. Double-stranded DNA molecules were tagged at sequence-specific motif sites with fluorescent bisPNA (Peptide Nucleic Acid) tags. The DNA molecules were then stretched in the microfluidic device and driven in a flow stream past confocal fluorescence detectors...
June 2004: Genome Research
https://www.readbyqxmd.com/read/14726665/genome-organization-in-three-dimensions-thinking-outside-the-line
#18
Rebecca A Haeusler, David R Engelke
Gene organization on nuclear chromosomes is usually depicted as a linear array, but at least some regions of the genome are localized to specific subnuclear positions in interphase nuclei. Studies in yeast have found that centromeres and telomeres are found around the nuclear periphery, and that tRNA genes are gathered at the nucleolus, along with the ribosomal RNA gene cluster. These 325 loci alone impose significant constraints on the three dimensional organization of chromosomes in the nucleus, and there is mounting experimental evidence that transcription by RNA polymerase II is strongly affected by proximity to these regions...
March 2004: Cell Cycle
https://www.readbyqxmd.com/read/14631041/nucleolar-clustering-of-dispersed-trna-genes
#19
Martin Thompson, Rebecca A Haeusler, Paul D Good, David R Engelke
Early transfer RNA (tRNA) processing events in Saccharomyces cerevisiae are coordinated in the nucleolus, the site normally associated with ribosome biosynthesis. To test whether spatial organization of the tRNA pathway begins with nucleolar clustering of the genes, we have probed the subnuclear location of five different tRNA gene families. The results show that tRNA genes, though dispersed in the linear genome, colocalize with 5S ribosomal DNA and U14 small nucleolar RNA at the nucleolus. Nucleolar localization requires tRNA gene transcription-complex formation, because inactivation of the promoter at a single locus removes its nucleolar association...
November 21, 2003: Science
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