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Featured researches published by Krister Bamberg.


Cell Metabolism | 2013

Gut Microbiota Regulates Bile Acid Metabolism by Reducing the Levels of Tauro-beta-muricholic Acid, a Naturally Occurring FXR Antagonist

Sama Islam Sayin; Annika Wahlström; Jenny Felin; Sirkku Jäntti; Hanns-Ulrich Marschall; Krister Bamberg; Bo Angelin; Tuulia Hyötyläinen; Matej Orešič; Fredrik Bäckhed

Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum.


Structure | 2001

Structure of the PPARα and -γ Ligand Binding Domain in Complex with AZ 242; Ligand Selectivity and Agonist Activation in the PPAR Family

Philippe Cronet; Jens Petersen; Rutger H. A. Folmer; Niklas Blomberg; Kristina Sjöblom; Ulla Karlsson; Eva-Lotte Lindstedt; Krister Bamberg

Abstract Background: The peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear receptor family. The roles of PPARα in fatty acid oxidation and PPARγ in adipocyte differentiation and lipid storage have been characterized extensively. PPARs are activated by fatty acids and eicosanoids and are also targets for antidyslipidemic drugs, but the molecular interactions governing ligand selectivity for specific subtypes are unclear due to the lack of a PPARα ligand binding domain structure. Results: We have solved the crystal structure of the PPARα ligand binding domain (LBD) in complex with the combined PPARα and -γ agonist AZ 242, a novel dihydro cinnamate derivative that is structurally different from thiazolidinediones. In addition, we present the crystal structure of the PPARγ_LBD/AZ 242 complex and provide a rationale for ligand selectivity toward the PPARα and -γ subtypes. Heteronuclear NMR data on PPARα in both the apo form and in complex with AZ 242 shows an overall stabilization of the LBD upon agonist binding. A comparison of the novel PPARα/AZ 242 complex with the PPARγ/AZ 242 complex and previously solved PPARγ structures reveals a conserved hydrogen bonding network between agonists and the AF2 helix. Conclusions: The complex of PPARα and PPARγ with the dual specificity agonist AZ 242 highlights the conserved interactions required for receptor activation. Together with the NMR data, this suggests a general model for ligand activation in the PPAR family. A comparison of the ligand binding sites reveals a molecular explanation for subtype selectivity and provides a basis for rational drug design.


The EMBO Journal | 2005

Regulation of hepatic metabolic pathways by the orphan nuclear receptor SHP

Konstantinos Boulias; Nitsa Katrakili; Krister Bamberg; Peter Underhill; Andy Greenfield; Iannis Talianidis

SHP (small heterodimer partner) is an important component of the feedback regulatory cascade, which controls the conversion of cholesterol to bile acids. In order to identify the bona fide molecular targets of SHP, we performed global gene expression profiling combined with chromatin immunoprecipitation assays in transgenic mice constitutively expressing SHP in the liver. We demonstrate that SHP affects genes involved in diverse biological pathways, and in particular, several key genes involved in consecutive steps of cholesterol degradation, bile acid conjugation, transport and lipogenic pathways. Sustained expression of SHP leads to the depletion of hepatic bile acid pool and a concomitant accumulation of triglycerides in the liver. The mechanism responsible for this phenotype includes SHP‐mediated direct repression of downstream target genes and the bile acid sensor FXRα, and an indirect activation of PPARγ and SREBP‐1c genes. We present evidence for the role of altered chromatin configurations in defining distinct gene‐specific mechanisms by which SHP mediates differential transcriptional repression. The multiplicity of genes under its control suggests that SHP is a pleiotropic regulator of diverse metabolic pathways.


PLOS ONE | 2013

Ageing Fxr Deficient Mice Develop Increased Energy Expenditure, Improved Glucose Control and Liver Damage Resembling NASH

Mikael Bjursell; Marianne Wedin; Therese Admyre; Majlis Hermansson; Gerhard Böttcher; Melker Göransson; Daniel Lindén; Krister Bamberg; Jan Oscarsson; Mohammad Bohlooly-Y

Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR) is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow diet. The Fxr deficient mice were similar to wild type mice in terms of body weight, body composition, energy intake and expenditure as well as behaviours at a young age. However, from 15 weeks of age and onwards, the Fxr deficient mice had almost no body weight increase up to 39 weeks of age mainly because of lower body fat mass. The lower body weight gain was associated with increased energy expenditure that was not compensated by increased food intake. Fasting levels of glucose and insulin were lower and glucose tolerance was improved in old and lean Fxr deficient mice. However, the Fxr deficient mice displayed significantly increased liver weight, steatosis, hepatocyte ballooning degeneration and lobular inflammation together with elevated plasma levels of ALT, bilirubin and bile acids, findings compatible with non-alcoholic steatohepatitis (NASH) and cholestasis. In conclusion, ageing Fxr deficient mice display late onset leanness associated with elevated energy expenditure and improved glucose control but develop severe NASH-like liver pathology.


PLOS ONE | 2017

Nephropathy in Pparg-null mice highlights PPARγ systemic activities in metabolism and in the immune system.

Barbara Toffoli; Federica Gilardi; Carine Winkler; Magnus Soderberg; Laura Kowalczuk; Yvan Arsenijevic; Krister Bamberg; Olivier Bonny; Béatrice Desvergne

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor involved in many aspects of metabolism, immune response, and development. Total-body deletion of the two Pparg alleles provoked generalized lipoatrophy along with severe type 2 diabetes. Herein, we explore the appearance and development of structural and functional alterations of the kidney, comparing Pparg null-mice to their littermate controls (carrying Pparg floxed alleles). We show that renal hypertrophy and functional alterations with increased glucosuria and albuminuria are already present in 3 weeks-old Pparg null-mice. Renal insufficiency with decreased creatinine clearance progress at 7 weeks of age, with the advance of the type 2 diabetes. At 52 weeks of age, these alterations are accompanied by signs of fibrosis and mesangial expansion. More intriguingly, aged Pparg null-mice concomitantly present an anti-phospholipid syndrome (APS), characterized by the late appearance of microthrombi and a mesangioproliferative pattern of glomerular injury, associated with significant plasmatic levels of anti-β2- glycoprotein1 antibodies and renal deposition of IgG, IgM, and C3. Thus, in line with the role of PPARγ in metabolic homeostasis, Pparg null-mice first represent a potent model for studying the initiation and the development of diabetic nephropathy. Second, and in relation with the important PPARγ activity in inflammation and in immune system, these mice also highlight a new role for PPARγ signaling in the promotion of APS, a syndrome whose pathogenesis is poorly known and whose current treatment is limited to prevention of thrombosis events.


ChemMedChem | 2017

Structure-Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity.

Anneli Nordqvist; Maria Fridén-Saxin; Marlene Fredenwall; Anders Hogner; Kenneth Granberg; Anna Aagaard; Stefan Bäckström; Anders Gunnarsson; Tim Kaminski; Yafeng Xue; Anita Dellsén; Eva L. Hansson; Pia Hansson; Ida Ivarsson; Ulla Karlsson; Krister Bamberg; Majlis Hermansson; Jennie Georgsson; Bo Lindmark; Karl Edman

The mineralocorticoid receptor (MR) is a nuclear hormone receptor involved in the regulation of body fluid and electrolyte homeostasis. In this study we explore selectivity triggers for a series of nonsteroidal MR antagonists to improve selectivity over other members of the oxosteroid receptor family. A biaryl sulfonamide compound was identified in a high‐throughput screening (HTS) campaign. The compound bound to MR with pKi=6.6, but displayed poor selectivity over the glucocorticoid receptor (GR) and the progesterone receptor (PR). Following X‐ray crystallography of MR in complex with the HTS hit, a compound library was designed that explored an induced‐fit hypothesis that required movement of the Met852 side chain. An improvement in MR selectivity of 11‐ to 79‐fold over PR and 23‐ to 234‐fold over GR was obtained. Given the U‐shaped binding conformation, macrocyclizations were explored, yielding a macrocycle that bound to MR with pKi=7.3. Two protein–ligand X‐ray structures were determined, confirming the hypothesized binding mode for the designed compounds.


The Journal of Physiology | 2018

Na restriction activates epithelial Na channels in rat kidney through two mechanisms and decreases distal Na+ delivery

Gustavo Frindt; Lei Yang; Krister Bamberg; Lawrence G. Palmer

Dietary Na restriction, through the mineralocorticoid aldosterone, acts on epithelial Na channels via both fast (24 h) and slow (5–7 days) mechanisms in the kidney. The fast effect entails increased proteolytic processing and trafficking of channel protein to the apical membrane. It is rapidly reversible by the mineralocorticoid receptor antagonist eplerenone and is largely lost when tubules are studied ex vivo. The slow effect does not require increased processing or surface expression, is refractory to acute eplerenone treatment, and is preserved ex vivo. Both slow and fast effects contribute to Na retention in vivo. Increased Na+ reabsorption in the proximal tubule also promotes Na conservation under conditions of chronic dietary Na restriction, reducing Na+ delivery to the distal nephron.


British Journal of Clinical Pharmacology | 2018

Clinical safety, tolerability, pharmacokinetics and effects on urinary electrolyte excretion of AZD9977, a novel, selective mineralocorticoid receptor modulator

Fredrik Erlandsson; Muna Albayaty; Ligia Chialda; Hans Ericsson; Carl Amilon; Karin Nelander; Rasmus Jansson-Löfmark; Linda Wernevik; Magnus Kjaer; Krister Bamberg; Judith Hartleib-Geschwindner

AZD9977 is the first mineralocorticoid receptor modulator in clinical development exerting similar organ protection as eplerenone with minimal urinary electrolyte effects in preclinical studies. The aim was to perform the initial clinical assessment of AZD9977.


Molecular Endocrinology | 2003

On the Role of Liver X Receptors in Lipid Accumulation in Adipocytes

Lene Kristine Juvet; Sissel Mahle Andresen; Gertrud U. Schuster; Knut Tomas Dalen; Kari Anne Risan Tobin; Kristin Hollung; Fred Haugen; Severina Jacinto; Stine M. Ulven; Krister Bamberg; Jan-Åke Gustafsson; Hilde I. Nebb


Physiological Genomics | 2005

Gene expression analysis suggests that EBF-1 and PPAR gamma 2 induce adipogenesis of NIH-3T3 cells with similar efficiency and kinetics

Peter Åkerblad; Robert Månsson; Anna Lagergren; Simonetta Westerlund; Barbro Basta; Ulrika Lind; Anders Thelin; Ramiro Gisler; David Liberg; Sven Nelander; Krister Bamberg; Mikael Sigvardsson

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