Differential regulation of intestinal efflux transporters by pregnancy in mice

Moscovitz, Jamie E.; Yarmush, Gabriel; Herrera-Garcia, Guadalupe; Guo, Grace L.; Aleksunes, Lauren M.

doi:10.1080/00498254.2016.1250292

Cited by 7 publications

(4 citation statements)

References 46 publications

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“…Gene expression of FXR targets was therefore examined in the liver and distal ileum. Confirming previous studies from our group (36, 44) and others (40), expression of FXR targets in the liver and distal ileum is reduced in pregnancy (Fig. 7, A and C ).…”

Section: Resultssupporting

confidence: 92%

Obeticholic acid ameliorates dyslipidemia but not glucose tolerance in mouse model of gestational diabetes

McIlvride

Nikolova

Fan

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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Metabolism alters markedly with advancing gestation, characterized by progressive insulin resistance, dyslipidemia, and raised serum bile acids. The nuclear receptor farnesoid X receptor (FXR) has an integral role in bile acid homeostasis and modulates glucose and lipid metabolism. FXR is known to be functionally suppressed in pregnancy. The FXR agonist, obeticholic acid (OCA), improves insulin sensitivity in patients with type 2 diabetes with nonalcoholic fatty liver disease. We therefore hypothesized that OCA treatment during pregnancy could improve disease severity in a mouse model of gestational diabetes mellitus (GDM). C57BL/6J mice were fed a high-fat diet (HFD; 60% kcal from fat) for 4 wk before and throughout pregnancy to induce GDM. The impact of the diet supplemented with 0.03% OCA throughout pregnancy was studied. Pregnant HFD-fed mice displayed insulin resistance and dyslipidemia. OCA significantly reduced plasma cholesterol concentrations in nonpregnant and pregnant HFD-fed mice (by 22.4%, P < 0.05 and 36.4%, P < 0.001, respectively) and reduced the impact of pregnancy on insulin resistance but did not change glucose tolerance. In nonpregnant HFD-fed mice, OCA ameliorated weight gain, reduced mRNA expression of inflammatory markers in white adipose tissue, and reduced plasma glucagon-like peptide 1 concentrations (by 62.7%, P < 0.01). However, these effects were not evident in pregnant mice. OCA administration can normalize plasma cholesterol levels in a mouse model of GDM. However, the absence of several of the effects of OCA in pregnant mice indicates that the agonistic action of OCA is not sufficient to overcome many metabolic consequences of the pregnancy-associated reduction in FXR activity.

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Section: Resultssupporting

confidence: 92%

Obeticholic acid ameliorates dyslipidemia but not glucose tolerance in mouse model of gestational diabetes

McIlvride

Nikolova

Fan

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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“…Indeed, we have previously shown that bile acid overload in the intestine of CA-fed mice increases FXR activity in the gut-liver axis, evidenced by repression of hepatic expression of Cyp7a1 29 . Intestinal FXR signalling has been shown to be reduced in mouse and human pregnancy 30 , 31 , 39 . FXR activity is thought to be reduced further in ICP due to the increase in circulating sulphated progesterone metabolites which are partial agonists of FXR 22 .…”

Section: Discussionmentioning

confidence: 99%

Maternal glucose homeostasis is impaired in mouse models of gestational cholestasis

Bellafante

McIlvride

Nikolova

et al. 2020

Sci Rep

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Women with intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by raised serum bile acids, are at increased risk of developing gestational diabetes mellitus and have impaired glucose tolerance whilst cholestatic. FXR and TGR5 are modulators of glucose metabolism, and FXR activity is reduced in normal pregnancy, and further in ICP. We aimed to investigate the role of raised serum bile acids, FXR and TGR5 in gestational glucose metabolism using mouse models. Cholic acid feeding resulted in reduced pancreatic β-cell proliferation and increased apoptosis in pregnancy, without altering insulin sensitivity, suggesting that raised bile acids affect β-cell mass but are insufficient to impair glucose tolerance. Conversely, pregnant Fxr −/− and Tgr5 −/− mice are glucose intolerant and have reduced insulin secretion in response to glucose challenge, and Fxr −/− mice are also insulin resistant. Furthermore, fecal bile acids are reduced in pregnant Fxr −/− mice. Lithocholic acid and deoxycholic acid, the principal ligands for TGR5, are decreased in particular. Therefore, we propose that raised serum bile acids and reduced FXR and TGR5 activity contribute to the altered glucose metabolism observed in ICP.

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“…Jamie E Moscovitz et al also examined, in addition to P-gp, intestinal BCRP mRNA and protein levels in mice during gestation. The results show that on days 14 and 19 of pregnancy, BCRP mRNA expression increased, but the results were not statistically significant, while on day 17 of pregnancy, BCRP mRNA and protein levels decreased significantly compared to the controls [78]. Wang et al, who examined BCRP expression in the placenta, also examined it in pregnant mouse small intestines.…”

Section: Expression Of Bcrp In the Small Intestine During Pregnancymentioning

confidence: 99%

“…They found that the Mdr1a mRNA levels decreased on days 14 and 17 of gestation and increased on day 19 of gestation. The expression of P-gp decreased on gestation day 17 by 70% in pregnant mice compared to the non-pregnant group [78]. Mathias et al also examined the intestinal P-gp protein expression in pregnant mice, but they found no significant differences between pregnant and non-pregnant mice [79].…”

Section: Expression Of P-gp In the Small Intestine During Pregnancymentioning

confidence: 99%

Changes in Expression and Function of Placental and Intestinal P-gp and BCRP Transporters during Pregnancy

Szatmári,

Ducza

2023

IJMS

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ABC transporters are ubiquitous in the human body and are responsible for the efflux of drugs. They are present in the placenta, intestine, liver and kidney, which are the major organs that can affect the pharmacokinetic and pharmacologic properties of drugs. P-gp and BCRP transporters are the best-characterized transporters in the ABC superfamily, and they have a pivotal role in the barrier tissues due to their efflux mechanism. Moreover, during pregnancy, drug efflux is even more important because of the developing fetus. Recent studies have shown that placental and intestinal ABC transporters have great importance in drug absorption and distribution. Placental and intestinal P-gp and BCRP show gestational-age-dependent expression changes, which determine the drug concentration both in the mother and the fetus during pregnancy. They may have an impact on the efficacy of antibiotic, antiviral, antihistamine, antiemetic and oral antidiabetic therapies. In this review, we would like to provide an overview of the pharmacokinetically relevant expression alterations of placental and intestinal ABC transporters during pregnancy.

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Differential regulation of intestinal efflux transporters by pregnancy in mice

Cited by 7 publications

References 46 publications

Obeticholic acid ameliorates dyslipidemia but not glucose tolerance in mouse model of gestational diabetes

Obeticholic acid ameliorates dyslipidemia but not glucose tolerance in mouse model of gestational diabetes

Maternal glucose homeostasis is impaired in mouse models of gestational cholestasis

Changes in Expression and Function of Placental and Intestinal P-gp and BCRP Transporters during Pregnancy

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