Shadi Abu-Hayyeh

Imperial College London, Londinium, England, United Kingdom

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Publications (14)106.02 Total impact

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    ABSTRACT: Intrahepatic Cholestasis of Pregnancy (ICP) is associated with an increased risk of fetal morbidity and mortality and is characterised by elevated bile acids in the maternal and fetal compartments. Bile acids have been shown to attenuate renal 11βHSD2 expression and, given the protective role of placental 11βHSD2 in preventing fetal exposure to excessive maternal cortisol, we aimed to establish whether raised serum bile acids in ICP influence placental 11βHSD2 expression. Placental tissue from human and murine cholestatic pregnancy was evaluated for changes in 11βHSD2 mRNA expression compared to uncomplicated pregnancy using quantitative PCR. Parallel in vitro studies were performed using BeWo choriocarcinoma cells to assess the effect of different bile acid species on 11βHSD2 gene expression and whether concurrent UDCA administration can reverse any bile acid induced changes. Placental 11βHSD2 mRNA expression was reduced in human and murine cholestatic pregnancy. In BeWo cells, treatment with the primary bile acid CDCA resulted in reduced 11βHSD2 gene expression, while treatment with other primary bile acids had no significant effect. Furthermore, the tertiary bile acid UDCA, used in the treatment of ICP did not significantly affect 11βHSD2 mRNA levels either alone, or when co-administered with CDCA. Under cholestatic conditions placental 11βHSD2 mRNA is reduced. Studies in BeWo choriocarcinoma cells demonstrated that CDCA is likely to be the specific bile acid that mediates this effect. UDCA, the main bile acid used to treat cholestasis, did not reduce placental 11βHSD2 expression, further supporting its use in the management of ICP.
    Placenta 11/2013; · 3.12 Impact Factor
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    ABSTRACT: The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.
    The Journal of clinical investigation 07/2013; 123(7):3172-81. · 15.39 Impact Factor
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    ABSTRACT: Bile acids have been traditionally thought of as having an important role in fat emulsification. It is now emerging that they act as important signalling molecules that not only autoregulate their own synthesis but also influence lipid and glucose metabolism. Although, the mechanisms that underlie the regulation of bile acid homeostasis have been well characterised in normal physiology, the impact of pregnancy on bile acid regulation is still poorly understood. This review summarises the main regulatory mechanisms underlying bile acid homeostasis and discusses how pregnancy, a unique physiological state, can modify them. The fetoplacental adaptations that protect against fetal bile acid toxicity are reviewed. We highlight the importance of bile acid regulation during gestation by discussing the liver disease of pregnancy, intrahepatic cholestasis of pregnancy (ICP) and how genetic, endocrine and environmental factors contribute to the disease aetiology at a cellular and molecular level.
    Molecular and Cellular Endocrinology 11/2012; · 4.04 Impact Factor
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    ABSTRACT: Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy-specific liver disease and is associated with an increased risk of adverse fetal outcomes, including preterm labor and intrauterine death. The endocrine signals that cause cholestasis are not known but 3α-sulfated progesterone metabolites have been shown to be elevated in ICP leading us to study the impact of sulfated progesterone metabolites on farnesoid x receptor (FXR) mediated bile acid homeostasis pathways. Here we report that the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate is supraphysiologically raised in the serum of ICP patients. Mice challenged with cholic acid developed hypercholanemia and a hepatic gene expression profile indicative of FXR activation. However, co-administration of epiallopregnanolone sulfate with cholic acid exacerbated the hypercholanemia and resulted in aberrant gene expression profiles for hepatic bile acid-responsive genes consistent with cholestasis. We demonstrate that levels of epiallopregnanolone sulfate found in ICP can function as a partial agonist for FXR,resulting in the aberrant expression of bile acid homeostasis genes in hepatoma cell lines and primary human hepatocytes. Furthermore, epiallopregnanolone sulfate inhibition of FXR results in reduced FXR-mediated bile acid efflux and secreted FGF19. Using co-factor recruitment assays, we show that epiallopregnanolone sulfate competitively inhibits bile acid-mediated recruitment of co-factor motifs to the FXR-ligand binding domain. Conclusion: Our results reveal a novel molecular interaction between ICP-associated levels of the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate and FXR that couples the endocrine component of pregnancy in ICP to abnormal bile acid homeostasis. (HEPATOLOGY 2012.).
    Hepatology 09/2012; · 12.00 Impact Factor
  • The Lancet 12/2011; 378(9807):1974. · 39.21 Impact Factor
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    ABSTRACT: Intrahepatic cholestasis of pregnancy (ICP) is complicated by spontaneous preterm labor, fetal anoxia and unexplained fetal death. We aim to evaluate the mechanisms by which raised fetal bile acids cause placental abnormalities and fetal cardiac pathology. The study was performed using placental samples taken from ICP pregnancies, placental explant culture, neonatal and adult cardiomyocytes, and murine and human embryonic stem cell-derived cardiomyocytes. Maternal cholestasis causes a placental phenotype with histological abnormalities. This can be evaluated using placental explant cultures. Taurocholate, the principal bile acid raised in the fetal compartment in ICP, causes abnormal cardiomyocyte contraction, rhythm and desynchronization of calcium dynamics. To extend our observations that the muscarinic M2 receptor plays a role in bile acid-induced arrhythmia in cardiomyocytes, we are developing a model containing mixed cell populations to represent the fetal and maternal hearts. This will be used to evaluate the underlying mechanisms to explain fetal arrhythmia in the presence of cholestasis. Bile acids signal via a spectrum of pathways in the placenta and the fetal heart.
    Digestive Diseases 01/2011; 29(1):58-61. · 2.73 Impact Factor
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    ABSTRACT: LKB1 is a 'master' protein kinase implicated in the regulation of metabolism, cell proliferation, cell polarity and tumorigenesis. However, the long-term role of LKB1 in hepatic function is unknown. In the present study, it is shown that hepatic LKB1 plays a key role in liver cellular architecture and metabolism. We report that liver-specific deletion of LKB1 in mice leads to defective canaliculi and bile duct formation, causing impaired bile acid clearance and subsequent accumulation of bile acids in serum and liver. Concomitant with this, it was found that the majority of BSEP (bile salt export pump) was retained in intracellular pools rather than localized to the canalicular membrane in hepatocytes from LLKB1KO (liver-specific Lkb1-knockout) mice. Together, these changes resulted in toxic accumulation of bile salts, reduced liver function and failure to thrive. Additionally, circulating LDL (low-density lipoprotein)-cholesterol and non-esterified cholesterol levels were increased in LLKB1KO mice with an associated alteration in red blood cell morphology and development of hyperbilirubinaemia. These results indicate that LKB1 plays a critical role in bile acid homoeostasis and that lack of LKB1 in the liver results in cholestasis. These findings indicate a novel key role for LKB1 in the development of hepatic morphology and membrane targeting of canalicular proteins.
    Biochemical Journal 01/2011; 434(1):49-60. · 4.65 Impact Factor
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    ABSTRACT: Nuclear receptor signalling is essential for physiological processes such as metabolism, development, and reproduction. Alterations in the endocrine state that naturally occur during pregnancy result in maternal adaptations to support the feto-placental unit. A series of studies have shown that nuclear receptor signalling is involved in maternal adaptations of bile acid, cholesterol, and lipid homeostasis pathways to ensure maintenance of the nutritional demands of the fetus. We discuss regulation of hepatic nuclear receptors and their target genes in pregnancy and their impact on the development of disorders such as intrahepatic cholestasis of pregnancy and oestrogen-induced hepatotoxicity. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.
    Biochimica et Biophysica Acta 11/2010; 1812(8):879-87. · 4.66 Impact Factor
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    ABSTRACT: Sulfated progesterone metabolite (P4-S) levels are raised in normal pregnancy and elevated further in intrahepatic cholestasis of pregnancy (ICP), a bile acid-liver disorder of pregnancy. ICP can be complicated by preterm labor and intrauterine death. The impact of P4-S on bile acid uptake was studied using two experimental models of hepatic uptake of bile acids, namely cultured primary human hepatocytes (PHH) and Na(+)-taurocholate co-transporting polypeptide (NTCP)-expressing Xenopus laevis oocytes. Two P4-S compounds, allopregnanolone-sulfate (PM4-S) and epiallopregnanolone-sulfate (PM5-S), reduced [(3)H]taurocholate (TC) uptake in a dose-dependent manner in PHH, with both Na(+)-dependent and -independent bile acid uptake systems significantly inhibited. PM5-S-mediated inhibition of TC uptake could be reversed by increasing the TC concentration against a fixed PM5-S dose indicating competitive inhibition. Experiments using NTCP-expressing Xenopus oocytes confirmed that PM4-S/PM5-S are capable of competitively inhibiting NTCP-mediated uptake of [(3)H]TC. Total serum PM4-S + PM5-S levels were measured in non-pregnant and third trimester pregnant women using liquid chromatography-electrospray tandem mass spectrometry and were increased in pregnant women, at levels capable of inhibiting TC uptake. In conclusion, pregnancy levels of P4-S can inhibit Na(+)-dependent and -independent influx of taurocholate in PHH and cause competitive inhibition of NTCP-mediated uptake of taurocholate in Xenopus oocytes.
    Journal of Biological Chemistry 02/2010; 285(22):16504-12. · 4.65 Impact Factor
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    ABSTRACT: Intrahepatic cholestasis of pregnancy (ICP) is a common disease affecting up to 5% of pregnancies and which can cause fetal arrhythmia and sudden intrauterine death. We previously demonstrated that bile acid taurocholate (TC), which is raised in the bloodstream of ICP, can acutely alter the rate and rhythm of contraction and induce abnormal calcium destabilization in cultured neonatal rat cardiomyocytes (NRCM). Apart from their hepatic functions bile acids are ubiquitous signalling molecules with diverse systemic effects mediated by either the nuclear receptor FXR or by a recently discovered G-protein coupled receptor TGR5. We aim to investigate the mechanism of bile-acid induced arrhythmogenic effects in an in-vitro model of the fetal heart. Levels of bile acid transporters and nuclear receptor FXR were studied by quantitative real time PCR, western blot and immunostaining, which showed low levels of expression. We did not observe functional involvement of the canonical receptors FXR and TGR5. Instead, we found that TC binds to the muscarinic M(2) receptor in NRCM and serves as a partial agonist of this receptor in terms of inhibitory effect on intracellular cAMP and negative chronotropic response. Pharmacological inhibition and siRNA-knockdown of the M(2) receptor completely abolished the negative effect of TC on contraction, calcium transient amplitude and synchronisation in NRCM clusters. We conclude that in NRCM the TC-induced arrhythmia is mediated by the partial agonism at the M(2) receptor. This mechanism might serve as a promising new therapeutic target for fetal arrhythmia.
    PLoS ONE 01/2010; 5(3):e9689. · 3.53 Impact Factor
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    ABSTRACT: Embryonic stem cell-derived cardiomyocytes (ESC-CM) have many of the phenotypic properties of authentic cardiomyocytes, and great interest has been shown in their possibilities for modelling human disease. Obstetric cholestasis affects 1 in 200 pregnant women in the United Kingdom. It is characterized by raised serum bile acids and complicated by premature delivery and unexplained fetal death at late gestation. It has been suggested that the fetal death is caused by the enhanced arrhythmogenic effect of bile acids in the fetal heart, and shown that neonatal susceptibility to bile acid-induced arrhythmia is lost in the adult rat cardiomyocyte. However, the mechanisms of the observed bile acid effects are not fully understood and their in vivo study in human beings is difficult. Here we use ESC-CM from both human and mouse ESCs to test our proposal that immature cardiomyocytes are more susceptible to the effect of raised bile acids than mature ones. We show that early ESC-CM exhibit bile acid-induced disruption of rhythm, depression of contraction and desynchronization of cell coupling. In both species the ESC-CM become resistant to these arrhythmias as the cells mature, and this develops in line with the respective gestational periods of mouse and human. This represents the first demonstration of the use of ESC-CM as a model system for human cardiac pathology, and opens the way for both investigation of mechanisms and a high throughput screen for drug discovery.
    Journal of Cellular and Molecular Medicine 04/2009; 13(9B):3730-41. · 4.75 Impact Factor
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    ABSTRACT: The fibroblast growth factors (FGFs) are key regulators of embryonic development, tissue homeostasis and tumour angiogenesis. Binding of FGFs to their receptor(s) results in activation of several intracellular signalling cascades including phosphoinositide 3-kinase (PI3K) and phospholipase C (PLC)gamma1. Here we investigated the basic FGF (FGF-2)-mediated activation of these enzymes in human umbilical vein endothelial cells (HUVECs) and defined their role in FGF-2-dependent cellular functions. We show that FGF-2 activates PLCgamma1 in HUVECs measured by analysis of total inositol phosphates production upon metabolic labelling of cells and intracellular calcium increase. We further demonstrate that FGF-2 activates PI3K, assessed by analysing accumulation of its lipid product phosphatidylinositol-3,4,5-P(3) using TLC and confocal microscopy analysis. PI3K activity is required for FGF-2-induced PLCgamma1 activation and the PI3K/PLCgamma1 pathway is involved in FGF-2-dependent cell migration, determined using Transwell assay, and in FGF-2-induced capillary tube formation (tubulogenesis assays in vitro). Finally we show that PI3K-dependent PLCgamma1 activation regulates FGF-2-mediated phosphorylation of Akt at its residue Ser473, determined by Western blotting analysis. This occurs through protein kinase C (PKC)alpha activation since dowregulation of PKCalpha expression using specific siRNA or blockade of its activity using chemical inhibition affects the FGF-2-dependent Ser473 Akt phosphorylation. Furthermore inhibition of PKCalpha blocks FGF-2-dependent cell migration. These data elucidate the role of PLCgamma1 in FGF-2 signalling in HUVECs demonstrating its key role in FGF-2-dependent tubulogenesis. Furthermore these data unveil a novel role for PLCgamma1 as a mediator of PI3K-dependent Akt activation and as a novel key regulator of different Akt-dependent processes.
    PLoS ONE 01/2009; 4(12):e8285. · 3.53 Impact Factor
  • Journal of Molecular and Cellular Cardiology - J MOL CELL CARDIOL. 01/2008; 44(4):774-775.
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    ABSTRACT: Novel and diverse functions of glial cells are currently the focus of much attention [A. Volterra and J. Meldolesi (2005) Nature Rev. 6, 626-640]. Here we present evidence that rat astroglia release acetylcholinesterase (AChE) as part of their response to hypoxic damage. Exposure of astroglia to tert-butyl hydroperoxide, and hence oxidative stress, subsequently leads to a switching in mRNA from the classical membrane-bound T-AChE to a preferential increase in the splice variant for a soluble form, R-AChE, This change in expression is reflected in increased perinuclear and reduced cytoplasmic AChE staining of the insulted glial cells, with a concomitant and marked increase in extracellular secretion that peaks at 1 h post-treatment. An analogous increase in R-AChE, over a similar time scale, occurs in response to psychological stress [D. Kaufer et al. (1998) Nature 93, 373-377], as well as to head injury and stroke [E. Shohami et al. (1999) J. Neurotrauma 6, 365-76]. The data presented here suggest that glial cells may be key chemical intermediaries in such situations and, perhaps more generally in pathological conditions involving oxidative stress, such as neurodegeneration.
    European Journal of Neuroscience 08/2006; 24(2):381-6. · 3.75 Impact Factor