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

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

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

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

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

6

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

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

7

8

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

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?

10

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

12

BAS Increases CA And Total CA Concentration In Serum

13

BAS Decreased Bile Acid Concentrations In Liver

14

Results: BAS increase CA proportion in liver Bile Acid Pool

15

Effects of Resin On Genes Involved in Bile Acid Homeostasis

16

Results: effects of Resin On Transcription Factors

Liver Intestine

Schematic Illustration Of Gene Regulation By BAS/Resin

Peizhen Song

18

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.

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

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