Metformin impairs bile acid homeostasis in ethinylestradiol-induced cholestasis in mice

Faradonbeh, Fatemeh Alaei; Igreja, Ivone Cristina; Lastuvkova, Hana; Cermanova, Jolana; Hroch, Miloš; Faistova, Hana; Mokrý, Jaroslav; Nová, Zuzana; Uher, Martin; Nachtigal, Petr; Pávek, Petr; Mičuda, Stanislav

doi:10.1016/j.cbi.2021.109525

Cited by 9 publications

(11 citation statements)

References 47 publications

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“…In agreement, our estrogen-treated WT rats showed a decrease in Ntcp, Oatp, Cyp7a1, Cyp8b1, and RXRa and activation of JNK and NF-kB. Similarly to previous results with ethinylestradiol-induced cholestasis, we also detected posttranscriptional reduction of Mrp2 ( Trauner et al, 1997 ; Lee et al, 2000 ; Wagner et al, 2003 ; Ruiz et al, 2007 ; Cermanova et al, 2015 ), Mrp4 upregulation ( Faradonbeh et al, 2021 ), and unchanged Bsep protein expression ( Ruiz et al, 2007 ). Cholestasis after ethinylestradiol is typically associated with ERa-JNK-c-JUN mediated ( Ruiz et al, 2013 ) upregulation of Mrp3 basolateral efflux transporter for BAs ( Hirsova et al, 2013 ; Muchova et al, 2015 ), which all were also reproduced in our study.…”

Section: Discussionsupporting

confidence: 92%

“…This indicates that reduced BA reabsorption in the intestine represents a compensatory mechanism to restore BA homeostasis during cholestasis ( Zhang et al, 2018 ). In agreement, reduced uptake of FXR agonistic BAs, such as CDCA and DCA, in the ileum led to reduced expression of target genes such as NR0B2 (Shp) and Fgf15 as also previously reported ( Hirsova et al, 2013 ; Faradonbeh et al, 2021 ).…”

Section: Discussionsupporting

confidence: 89%

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Multidrug Resistance-Associated Protein 2 Deficiency Aggravates Estrogen-Induced Impairment of Bile Acid Metabolomics in Rats

et al. 2022

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Multidrug resistance-associated protein 2 (Mrp2) mediates biliary secretion of anionic endobiotics and xenobiotics. Genetic alteration of Mrp2 leads to conjugated hyperbilirubinemia and predisposes to the development of intrahepatic cholestasis of pregnancy (ICP), characterized by increased plasma bile acids (BAs) due to mechanisms that are incompletely understood. Therefore, this study aimed to characterize BA metabolomics during experimental Mrp2 deficiency and ICP. ICP was modeled by ethinylestradiol (EE) administration to Mrp2-deficient (TR) rats and their wild-type (WT) controls. Spectra of BAs were analyzed in plasma, bile, and stool using an advanced liquid chromatography–mass spectrometry (LC–MS) method. Changes in BA-related genes and proteins were analyzed in the liver and intestine. Vehicle-administered TR rats demonstrated higher plasma BA concentrations consistent with reduced BA biliary secretion and increased BA efflux from hepatocytes to blood via upregulated multidrug resistance-associated protein 3 (Mrp3) and multidrug resistance-associated protein 4 (Mrp4) transporters. TR rats also showed a decrease in intestinal BA reabsorption due to reduced ileal sodium/bile acid cotransporter (Asbt) expression. Analysis of regulatory mechanisms indicated that activation of the hepatic constitutive androstane receptor (CAR)-Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by accumulating bilirubin may be responsible for changes in BA metabolomics in TR rats. Ethinylestradiol administration to TR rats further increased plasma BA concentrations as a result of reduced BA uptake and increased efflux via reduced Slco1a1 and upregulated Mrp4 transporters. These results demonstrate that Mrp2-deficient organism is more sensitive to estrogen-induced cholestasis. Inherited deficiency in Mrp2 is associated with activation of Mrp3 and Mrp4 proteins, which is further accentuated by increased estrogen. Bile acid monitoring is therefore highly desirable in pregnant women with conjugated hyperbilirubinemia for early detection of intrahepatic cholestasis.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 89%

Multidrug Resistance-Associated Protein 2 Deficiency Aggravates Estrogen-Induced Impairment of Bile Acid Metabolomics in Rats

et al. 2022

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“…The activations of BSEP and NTCP are beneficial for relieving the disorder of cholesterol metabolism by promoting the excretion of bile acids from the liver to the intestine. 78…”

Section: Resultsmentioning

confidence: 99%

“…The activations of BSEP and NTCP are beneficial for relieving the disorder of cholesterol metabolism by promoting the excretion of bile acids from the liver to the intestine. 78 In addition to improving the cholesterol metabolism, highdose GAA intervention also protected against alcoholic liver injury by regulating the mRNA transcription level of genes related to alcohol metabolism (ADH2, ALDH2 and CYP2E1). It is widely accepted that ADH2 is one of the key enzymes in alcohol metabolism and participates in the first-pass metabolism of ethanol in the human body.…”

Section: Papermentioning

confidence: 99%

Ganoderic acid A from Ganoderma lucidum protects against alcoholic liver injury through ameliorating the lipid metabolism and modulating the intestinal microbial composition

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et al. 2022

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“…After a 2-week adaptation period, the mice were administrated daily, for 5 days, subcutaneously (s.c.) with propanediol as the control group (C), ethinylestradiol (10 mg/kg s.c.) (EE) to induce intrahepatic cholestasis, labetalol (10 mg/kg s.c.) (L) or concomitant administration of ethinylestradiol (10 mg/kg) with labetalol (10 mg/kg s.c.) (EEL) simulating the antihypertensive treatment during intrahepatic cholestasis in pregnancy. Indeed, ethinylestradiol (the major estrogen sex hormone in humans and a widely used medication) is used for estrogen-induced cholestasis, an animal model for intrahepatic cholestasis of pregnancy ( Muchova et al, 2015 ; Faradonbeh et al, 2021 ; Gijbels et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Labetalol and soluble endoglin aggravate bile acid retention in mice with ethinylestradiol-induced cholestasis

et al. 2023

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Labetalol is used for the therapy of hypertension in preeclampsia. Preeclampsia is characterized by high soluble endoglin (sEng) concentration in plasma and coincides with intrahepatic cholestasis during pregnancy (ICP), which threatens the fetus with the toxicity of cumulating bile acids (BA). Therefore, we hypothesized that both labetalol and increased sEng levels worsen BA cumulation in estrogen-induced cholestasis. C57BL/6J, transgenic mice overexpressing human sEng, and their wild-type littermates were administrated with ethinylestradiol (EE, 10 mg/kg s.c., the mice model of ICP) and labetalol (10 mg/kg s.c.) for 5 days with sample collection and analysis. Plasma was also taken from healthy pregnant women and patients with ICP. Administration of labetalol to mice with EE cholestasis aggravated the increase in BA plasma concentrations by induction of hepatic Mrp4 efflux transporter. Labetalol potentiated the increment of sEng plasma levels induced by estrogen. Increased plasma levels of sEng were also observed in patients with ICP. Moreover, increased plasma levels of human sEng in transgenic mice aggravated estrogen-induced cholestasis in labetalol-treated mice and increased BA concentration in plasma via enhanced reabsorption of BAs in the ileum due to the upregulation of the Asbt transporter. In conclusion, we demonstrated that labetalol increases plasma concentrations of BAs in estrogen-induced cholestasis, and sEng aggravates this retention. Importantly, increased sEng levels in experimental and clinical forms of ICPs might present a novel mechanism explaining the coincidence of ICP with preeclampsia. Our data encourage BA monitoring in the plasma of pregnant women with preeclampsia and labetalol therapy.

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Metformin impairs bile acid homeostasis in ethinylestradiol-induced cholestasis in mice

Cited by 9 publications

References 47 publications

Multidrug Resistance-Associated Protein 2 Deficiency Aggravates Estrogen-Induced Impairment of Bile Acid Metabolomics in Rats

Multidrug Resistance-Associated Protein 2 Deficiency Aggravates Estrogen-Induced Impairment of Bile Acid Metabolomics in Rats

Ganoderic acid A from Ganoderma lucidum protects against alcoholic liver injury through ameliorating the lipid metabolism and modulating the intestinal microbial composition

Labetalol and soluble endoglin aggravate bile acid retention in mice with ethinylestradiol-induced cholestasis

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