4 th global summit on toxicology philadelphia, pa, usa aug. 24-26, 2015
TRANSCRIPT
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Invited Speaker:
Peizhen Song, PhD/MD4th Global Summit on ToxicologyPhiladelphia, PA, USAAug. 24-26, 2015
Effects Of Bile Acid Sequestration
On Bile Acid Profile And Bile Acid Signaling
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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.
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Bile Acid Sequestrant (BAS) or Resin
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Bile Acids(CA and CDCA)
Cholesterol
Liver
Po
rtal
Vei
n
Enterohepatic Circulation (EHC) and BAS Working Spot
Cy
7a
1
95%
(5%)
CA
DCA
CDCA
LCA
Bile AcidsIn Systemic
Blood
3
BAS increases defecation of
Bile
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Ntcp
Oatp1b2
Cyp7a
Cyp8b1
Bsep
Asbt
Mrp4
Mrp3
Ostα/β
Ostα/β
Hepatocyte Ileocyte
Bile Acid Transporters in Hepatocytes and Ileocytes Mediate Acitve EHC of Bile Acids
Sinusoid
Can
alic
ular
M
embr
ane
Basolateral Membrane
Basolateral Membrane
Apical Membrane
BloodIntestine
CanaliculusOatp1a4
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Bile Acids and Their Physiological Function
Facilitate:• The absorption of dietary fat• The elimination of cholesterol and some xenobiotics
Bile Acids: Classic Physiological Functions
Regulate:• Homeostasis of cholesterol, bile acids, fatty acids, and glucose
via activation of FXR, TGR5, etc.
Bile Acids: Novel Functions: Hormones
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FXR
SHP
Ntcp
Oatp1b2
Fgfr4
Cyp7a
Cyp8b1
Bsep
Asbt
Mrp4
Mrp3
Ostα/βOstα/β
HEPATOCYTEILEOCYTE
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
Bile Acids Regulate Their Own Homeostasis
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Biosynthesis of Bile Acids
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
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GLP-1
Increase Insulin Secretion
Inhibition of Appetites
Impaired Gastric Emptying
T4
T3 Increased Energy ExpenditureIncreased Body Temperature
Bile Acid Regulate Metabolism Via Cell Membrane Receptor: TGR5
L Cell In the gut
Brown Fat Tissues
TGR5
TGR5
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Normal Bile acid level in
the EHC pool
Bile acid regulation of metabolism
Bile acids Systemic
Homeostasis
?
?
Disrupted EHC by BAS
Will Disruption of EHC by BAS Result in Decreased Bile Acid Signaling In the Body?
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2% Cholestyramine resin supplemented diet
was used to feed mice (Male C57BL/6 mice (22 + 2g) at 8 weeks of age) for one week
Qualification of Bile acids concentration : liquid chromatography-tandem mass spectrometry
Qualification of mRNAs: QuantiGene Plex assay
Statistics: Differences between multiple groups were analyzed by one-way ANOVA followed by Duncan’s post hoc test. Statistical significance was considered at p < 0.05.
Methods
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BAS Decreased Total Bile Acid Concentration In Liver
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BAS Increases CA And Total CA Concentration In Serum
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BAS Decreased Bile Acid Concentrations In Liver
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Results: BAS increase CA proportion in liver Bile Acid Pool
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Effects of Resin On Genes Involved in Bile Acid Homeostasis
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Results: effects of Resin On Transcription Factors
Liver Intestine
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Schematic Illustration Of Gene Regulation By BAS/Resin
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Peizhen Song
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Highlights Of The Study:
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.
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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
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Acknowledgements
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Invited Speaker:
Peizhen Song, PhD/MD
Effects Of Bile Acid Sequestration
On Bile Acid Profile And Bile Acid Signaling ----The Bile Acid Sequestrant Decrease Bile Acid Signaling in
the EHC, But Enhances Systemic Bile Acid Signaling
4th Global Summit on Toxicology