4 th Global Summit on Toxicology Philadelphia, PA, USA Aug. 24-26, 2015.

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Presentation transcript:

4 th Global Summit on Toxicology Philadelphia, PA, USA Aug , 2015

 Cholesterol-lowering drugs BASs: - Cholestyramine (Questran, 1973), - Colesevelam (Welchol, 2000)  BASs Novel Utilities: Glycemic Control in T2D Patients In 2008, USA FDA Approved BASs as a Conjunct Medicine for the Treatment of T2D. 2 Bile Acid Sequestrant (BAS) or Resin

Bile Acids (CA and CDCA) Cholesterol Liver Portal Vein Enterohepatic Circulation (EHC) and BAS Working Spot Cy7a1 95% (5%) CA DCA CDCA LCA Bile Acids In Systemic Blood 3 BAS increases defecation of Bile

Ntcp Oatp1b2 Cyp7a Cyp8b1 Bsep Asbt Mrp4 Mrp3 Ostα/β Hepatocyte Ileocyte Bile Acid Transporters in Hepatocytes and Ileocytes Mediate Acitve EHC of Bile Acids Sinusoid Canalicular Membrane Basolateral Membrane Apical Membrane Blood Intestine Canaliculus Oatp1a4

Bile Acids: Classic Physiological Functions Bile Acids: Novel Functions: Hormones

6 FXR SHP Ntcp Oatp1b2 Fgfr4 Cyp7a Cyp8b1 Bsep Asbt Mrp4 Mrp3 Ostα/β H EPATOCYTE I LEOCYTE Systemic Blood Circulation GI Tract CSA Fgf15 FXR BA Fecal Excretion Increased signaling Increased Gene Expression Decreased Gene Expression Bile Acid Molecule Shp Inhibition Effects

Liver DCA LCA Intestine 12-OH Bile Acid species: CA and DCA Non-12-OH Bile Acid Species: CDCA and LCA Major BA biosynthesis pathways 7

8 GLP-1 Increase Insulin Secretion Inhibition of Appetites Impaired Gastric Emptying T4 T3 Increased Energy Expenditure Increased Body Temperature Bile Acid Regulate Metabolism Via Cell Membrane Receptor: TGR5 L Cell In the gut Brown Fat Tissues TGR5

Peizhen Song9 ? ? Disrupted EHC by BAS Will Disruption of EHC by BAS Result in Decreased Bile Acid Signaling In the Body?

10 Methods

11

12

13

14

15

16 Liver Intestine

Peizhen Song 18  The BAS Decreases Bile Acid Signaling inside EHC system (including the ileum and the liver)  The data suggest a possible third mechanisms for the Cholesterol-Lowering drug BASs: BAS increases the blood CA concentration, which can activate TGR5 causing increased metabolism of Sugar and Lipids.  The BAS Increased Bile Acid Concentration In Systemic Blood which may be responsible for increased metabolism of lipid and glucose.

University of Kansas, School of Medicine: Dr. Sara Li Dr. Johnason Li Fang Fan, PhD/MD Quality & Science Consulting: Boj Kong, Ph.D Ryan Wiley M.S 19 Acknowledgements

Toxicology 4 th Global Summit on Toxicology