Georgia Papacleovoulou, Vanessa Pataia, Vanya Nikolova and Catherine - - PowerPoint PPT Presentation

Georgia Papacleovoulou, Vanessa Pataia, Vanya Nikolova and Catherine Williamson

Maternal and Fetal Disease Group, Women’s Health, King’s College London

The Power of Programming 2014, 13th March 2014

Note: : for non non-com

• mmerci

mercial al purposes only



A liver-specific disease of pregnancy



Affects both the mother and the fetus Mother:

i)

Raised serum bile acids (BA)

ii)

Dyslipidaemia Fetus

i)

Impaired transfer of bile acids from the fetus to the mother

ii)

Accumulation of bile acids in the fetal circulation

BA Fxr BA Bsep

BA Uptake BA Secretion

Fxr Shp Cyp7a1 Cholesterol BA BA

Oatp1a1, b2, a4

 UDCA is used to treat cholestatic liver diseases and is the most common

treatment for ICP

 Experimental data suggest that UDCA protects the liver from

• BA cytotoxicity
• BA-induced apoptosis

 UDCA promotes hepatic excretion of BA  UDCA restores the impaired BA gradient across the placenta

Beuer ers; 3:318-28 28 Nat Clin Pract Gastroen

• enter

terol

• l Hepatol
• l,

, 2006 2006 Geenes es et al.; 9(1):e838 83828 28 Plos One, 2014

Parameter Control ICP

Male offspring

maternal BMI (kg/m2) 22.20 ± 0.05 22.19 ± 0.7 placenta weight (g) 655.40 ± 2.25 677.60 ± 30.3 birth weight (g) 3600 ± 1.04 3600 ± 113.8 hip girth (cm) 91.6 ± 0.14 95.5 ± 2.44 waist girth (cm) 75.6 ± 0.16 74.77 ± 4.31 BMI (kg/m2) 21.07 ± 0.06 23.63 ± 1.2* insulin (mU/L) 10.76 ± 0.13 23.60 ± 7.5* apolipoprotein B (mmol/L) 0.65 ± 0.003 0.69 ± 0.03 HDL-chol (mmol/L) 1.29 ± 0.006 1.34 ± 0.08 LDL-chol (mmol/L) 2.13 ± 0.01 2.30 ± 0.16

Female offspring

maternal BMI (kg/m2) 22.30 ± 0.05 22.50 ± 1.23 placenta weight (g) 645 ± 2.26 649 ± 29.9 birth weight (g) 3500 ± 12.2 3400 ± 104.9 hip girth (cm) 92.9 ± 0.13 96.7 ± 1.4* waist girth (cm) 71.8 ± 0.15 77.5 ± 2.3* BMI (kg/m2) 21.17 ± 0.05 22.44 ± 0.7 insulin (mU/L) 10.64 ± 0.11 10.08 ± 0.8 apolipoprotein B (mmol/L) 0.68 ± 0.16 0.71 ± 0.03 HDL-chol (mmol/L) 1.49 ± 0.05 1.36 ± 0.04* LDL-chol (mmol/L) 2.30 ± 0.01 2.36 ± 0.11 males: control n=4034; ICP n=27 females: control n=3774; ICP n=18 *p≤0.05

BMI (kg/ g/m2) 21.07 ± 0.06 23.63 ± 1.2* in insul ulin in (mU mU/L) 10.76 ± 0.13 23.60 ± 7.5* hip girth (cm) 92.9 ± 0.13 96.7 ± 1.4* waist girth (cm) 71.8 ± 0.15 77.5 ± 2.3* HDL-chol (mmol/L) 1.49 ± 0.05 1.36 ± 0.04* ICP and metabolic programming in the offspring

Papacleo eovou voulou

• u et al.;123(7)

7):3 :3172 172-81 81 J J Clin Invest est, 2013

F emale offspring exposed to high BA in utero develop metabolic disease

Papacleo eovou voulou

• u et al.;123(7)

7):3 :3172 172-81 81 J J Clin Invest est, 2013

Cholestatic pregnancy causes dyslipidaemia in the fetoplacental unit

Papacleo eovo voulou

• u et al.;123(7)

7):3 :3172 172-81 81 J J Clin Invest est, 2013

Mouse placen centa Mouse placen centa Human placen centa Human umbilica lical l cord d serum um

UDCA can be used as an intervention in ICP to correct BA- related fetoplacental dyslipidaemia and prevent metabolic disease in the offspring

Hypothesis

Administration of UDCA in cholestatic pregnancy

0.5% CA feeding 0.5% UDCA feeding Maternal liver, placenta, fetal liver Maternal and fetal serum

BA and lipid measurements Gene expression of metabolic genes

BA homeostasis Cholesterol homeostasis FA homeostasis

E ffect of UDCA on BA homeostasis in the maternal liver

Cyp7 p7a1 a1

Relative ive expression ion

NC CA CA+UDCA

Diet

Cyp7 p7a1 #

*

2 4 6 NC CA CA+UDCA Relative ive expres essio ion Diet

*

# Bsep

Fxr BA Fxr Shp Cyp7a1 Cholesterol BA BA

Relative ive expressio ion

Bsep

Mrp2

BA

E ffect of UDCA on BA transporters in the placenta

1 2 3 NC CA CA+UDCA Relative ive expres ession ion Diet

*

Mrp2

0,5 1 1,5 NC CA CA+UDCA Relative ive expres ession ion Diet

Oatp1 p1a4 a4

*

# #

1 2 3 NC CA CA+UDCA Relative ive expres ession ion Diet

Oatp1 p1a1 a1

2 4 6 8 10 12 NC CA CA+UDCA Relative ive expres ession ion Diet

Oatp1 p1b2 b2 # #

Maternal circulation Fetal circulation Placenta

Oatp1a1, b2, a4 Oatp1a1, b2, a4

E ffect of UDCA in lipid biosynthesis in the fetal liver

1 2 3 NC CA CA+UDCA Relative ive expres ession ion Diet

*

1 2 3 4 5 NC CA CA+UDCA Relative ive expres ession ion Diet

Hmgcr Fas

*

#

C

Hmgcr Fas

FA

Oatp1a1, b2, a4

Fxr Shp Cyp7a1 BA BA

Summary

0.5% CA feeding 0.5% UDCA feeding

Placenta

BA BA BA BA

Maternal liver Fetal liver

Maternal circulation Fetal circulation

C

Hmgcr Fas

C FA Bsep

Oatp1a1, b2, a4 Mrp2

Ongoing work

 Biochemical measurements to study the effect of UDCA

• n bile acids and lipids in the mother and the fetus

 Study the effects of UDCA on the lipid homeostasis

pathways in placenta and fetal liver

 To address the effects of administration of UDCA in

pregnancy on the long-term health of the offspring in mice and humans

Acknowledgements



Professor Catherine Williamson



Vanessa Pataia



Vanya Nikolova



Maternal and Fetal Disease group