Bile acid receptor FXR: metabolic regulator in the gut. Sungsoon Fang
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1 Bile acid receptor FXR: metabolic regulator in the gut Sungsoon Fang
2 Nuclear hormone receptor 1905: Ernest Starling coined hormone 1929: Estrogen structure 1958: Estrogen receptor by Elwood Jensen 1985: GR and ER genes were cloned by Evans and Chambon, Evolutionary conserved from c.elegans to human (48 NRs in human). 13% of FDA-approved drugs target nuclear receptors
3 Nuclear receptor family Endocrine Receptors High-affinity hormonal ligands Adopted Orphan Receptors Low-affinity dietary ligands Orphan Receptors Unknown ligands GR glucocorticoid MR mineralocorticoid ER, estrogen AR testosterone PR progesterone TR, thyroid hormone VDR vitamin D RAR,, retinoic acid LXR, oxysterols FXR bile acids PPAR,, fatty acids PXR xenobiotics CAR xenobiotics RXR,, 9-cis-RA SF-1 SHP TLX PNR LHR-1 DAX-1 GCNF HNF-4, TR2,4 ERR,, Rev-erb, ROR,, NGFI-B,, COUP-TF,, High-affinity hormonal ligands
4 Precise regulation of NR transcriptional activity Active repression Co-repressors recruit chromatin modifying enzymes (HDACs) Ligand-mediated activation Exchange repressive (HDACs) for activating enzymes (HATs) CARM1 + ligand
5 Diet is the factor to determine our physiology
6 Chronic Inflammation and Diabetes: Walking the Line Obesity Chronic Inflammation Diabetes
7 Targeting Metabolic syndromes Metabolic Diseases: Obesity* and Diabetes (Type II)* (Burns Fat improves Insulin resistance) Insulin therapy: feeding signal
8 FXR responds to feeding signals via BAs LIVER GALL BLADDER FXR BILE BLOOD INTESTINE Chylomicrons
9 Question: Does intestinal FXR regulate whole body metabolism?
10 FXR paradox: FXR KO mice: dyslipidemia, hyperglycemia FXR agonist: GW4064 acute treatment in normal chow improved glucose/lipid metabolism Ob/FXRKO: improved metabolic phenotypes FXRKO with HFD: improved metabolic phenotypes FXR agonist in DIO: more obese than control
11 Developing new ligands for FXR is promising to treat metabolic diseases
12 FXR paradox: Development of novel FXR agonists is required to avoid the adverse effects of FXR activation
13 Fexaramine Mol Cell, 2003 Structurally distinct from natural bile acids Distinct gene expression profiles compared to GW4064 or bile acids
14 Fex: intestinal specific-fxr agonist 5 days Serum collection Treatment (PO or IP) Oral gavage * ** ** * * ** LC/MS quantitation ** LC/MS quantitation FEX EC50 = 25nM Liver kidney ileum
15 Anti-obesity effects by FEX * * * * * * * * **
16 Enhanced energy expenditure in BAT by FEX FEX-treated mice consume more glucose and lipid as energy sources
17 OXPHOS gene changes normalized expression Enhanced energy expenditure in BAT by FEX ** Vehicle Fex iwat gwat BAT
18 Browning in white adipose tissues by FEX UCP1 staining ** Vehicle Fex
19 Reduced hepatic gluconeogenesis and lipogenesis Vehicle Fex * * * * * *
20 Fex improves glucose homeostasis Clamp study: heavier mice for fexaramine to prepare body weight-matched cohort (Olefsky lab) clamp GDR
21 Fexaramine effects Gluconeogenesis lipogenesis Inflammation Browning Energy expenditure
22 Fexaramine: Therapeutic strategy for treatment of T2D?
23 Is Fexaramine bariatric surgery mimetic? Weight loss Elevated FGF19 Decrease of TCA level Increase of CA level
24 Ileal FXR target genes Is gut-specific FXR agonism bariatric surgery mimetic? normalized expression (log 2 ) FGF15 Tsku Enpp7 Ttc36 Pck1 Per1 Slc5a12 Ace Homer2 Gadd45b Aqp1 Pcsk9 Ephx2 Ms4a10 Akr1c19 Tsc22d3 Cyp2d26 Treh Endod1 Tfrc Slc30a10 Gpnmb Lpl Fa2h Weight loss Elevated FGF19 Decrease of TCA level Increase of CA level FGF15 orthologue: FGF19 (human)
25 Is gut-specific FXR agonism bariatric surgery mimetic? BA composition (%) ωmca T-βMCA βmca αmca T-UDCA UDCA T-HDCA HDCA T-DCA DCA G-LCA LCA T-CDCA CDCA T-CA CA
26 Is gut-specific FXR agonism bariatric surgery mimetic? BA composition (%) ωmca T-βMCA βmca αmca T-UDCA UDCA T-HDCA HDCA T-DCA DCA G-LCA LCA T-CDCA CDCA T-CA CA Weight loss Elevated FGF19 Decrease of TCA level Increase of CA level
27 Fexaramine effects Gluconeogenesis lipogenesis Inflammation Browning Energy expenditure FGF15/19 BA composition changes Gut-specific FXR agonism: potent therapeutic strategy to treat metabolic syndromes
28 Acknowledgement Evans Lab Jaemyoung Suh & Eiji Yoshihara Liz Yu Annette Atkins Ruth Yu Michael Downes Ronald Evans The Salk Institute Mathias Leblanc University of California of San Diego Jerry Olefsky lab University of Michigan Alan Saltiel lab University of Sydney Christopher Liddle
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