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rebecca AND haeusler

Sei Higuchi, M Concepción Izquierdo, Rebecca A Haeusler
PURPOSE OF REVIEW: Type 2 diabetes is associated with a characteristic dyslipidemia that may exacerbate cardiovascular risk. The causes of, and the effects of new antihyperglycemia medications on, this dyslipidemia, are under investigation. In an unexpected reciprocal manner, lowering LDL-cholesterol with statins slightly increases the risk of diabetes. Here we review the latest findings. RECENT FINDINGS: The inverse relationship between LDL-cholesterol and diabetes has now been confirmed by multiple lines of evidence...
June 2018: Current Opinion in Lipidology
KyeongJin Kim, Ira J Goldberg, Mark J Graham, Meenakshi Sundaram, Enrico Bertaggia, Samuel X Lee, Li Qiang, Rebecca A Haeusler, Daniel Metzger, Pierre Chambon, Zemin Yao, Henry N Ginsberg, Utpal B Pajvani
Excess plasma triglycerides (TGs) are a key component of obesity-induced metabolic syndrome. We have shown that γ-secretase inhibitor (GSI) treatment improves glucose tolerance due to inhibition of hepatic Notch signaling but found additional Notch-independent reduction of plasma TG-rich lipoproteins (TRLs) in GSI-treated, as well as hepatocyte-specific, γ-secretase knockout (L-Ncst) mice, which suggested a primary effect on hepatocyte TRL uptake. Indeed, we found increased VLDL and LDL particle uptake in L-Ncst hepatocytes and Ncst-deficient hepatoma cells, in part through reduced γ-secretase-mediated low-density lipoprotein receptor (LDLR) cleavage and degradation...
April 3, 2018: Cell Metabolism
Samuel X Lee, Markus Heine, Christian Schlein, Rajasekhar Ramakrishnan, Jing Liu, Gabriella Belnavis, Ido Haimi, Alexander W Fischer, Henry N Ginsberg, Joerg Heeren, Franz Rinninger, Rebecca A Haeusler
Insulin resistance and type 2 diabetes are associated with low levels of high-density lipoprotein cholesterol (HDL-C). The insulin-repressible FoxO transcription factors are potential mediators of the effect of insulin on HDL-C. FoxOs mediate a substantial portion of insulin-regulated transcription, and poor FoxO repression is thought to contribute to the excessive glucose production in diabetes. In this work, we show that mice with liver-specific triple FoxO knockout (L-FoxO1,3,4), which are known to have reduced hepatic glucose production, also have increased HDL-C...
April 2, 2018: Journal of Clinical Investigation
Fanny Langlet, Rebecca A Haeusler, Daniel Lindén, Elke Ericson, Tyrrell Norris, Anders Johansson, Joshua R Cook, Kumiko Aizawa, Ling Wang, Christoph Buettner, Domenico Accili
Insulin resistance is a hallmark of diabetes and an unmet clinical need. Insulin inhibits hepatic glucose production and promotes lipogenesis by suppressing FOXO1-dependent activation of G6pase and inhibition of glucokinase, respectively. The tight coupling of these events poses a dual conundrum: mechanistically, as the FOXO1 corepressor of glucokinase is unknown, and clinically, as inhibition of glucose production is predicted to increase lipogenesis. Here, we report that SIN3A is the insulin-sensitive FOXO1 corepressor of glucokinase...
November 2, 2017: Cell
Rebecca A Haeusler, Timothy E McGraw, Domenico Accili
The mechanism of insulin action is a central theme in biology and medicine. In addition to the rather rare condition of insulin deficiency caused by autoimmune destruction of pancreatic β-cells, genetic and acquired abnormalities of insulin action underlie the far more common conditions of type 2 diabetes, obesity and insulin resistance. The latter predisposes to diseases ranging from hypertension to Alzheimer disease and cancer. Hence, understanding the biochemical and cellular properties of insulin receptor signalling is arguably a priority in biomedical research...
January 2018: Nature Reviews. Molecular Cell Biology
Enrico Bertaggia, Kristian K Jensen, Jose Castro-Perez, Yimeng Xu, Gilbert Di Paolo, Robin B Chan, Liangsu Wang, Rebecca A Haeusler
Bile acids (BAs) are cholesterol derivatives that regulate lipid metabolism, through their dual abilities to promote lipid absorption and activate BA receptors. However, different BA species have varying abilities to perform these functions. Eliminating 12α-hydroxy BAs in mice via Cyp8b1 knockout causes low body weight and improved glucose tolerance. The goal of this study was to determine mechanisms of low body weight in Cyp8b1-/- mice. We challenged Cyp8b1-/- mice with a Western-type diet and assessed body weight and composition...
August 1, 2017: American Journal of Physiology. Endocrinology and Metabolism
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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