The ileum-liver Farnesoid X Receptor signaling axis mediates the compensatory mechanism of 17α-ethynylestradiol-induced cholestasis via increasing hepatic biosynthesis of chenodeoxycholic acids in rats

Zhang, Fan; Xi, Lili; Duan, Yingting; Qin, Hong‐Yan; Wei, Mengmeng; Wu, Yao; Li, Boxia; Zhou, Yan; Wu, Xinan

doi:10.1016/j.ejps.2018.08.005

Cited by 13 publications

(6 citation statements)

References 47 publications

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“…CYP8B1 catalyzes the synthesis of CA and plays a central role in intestinal cholesterol absorption and cholesterol gallstones, dyslipidemia, and the pathogenesis of diabetes [21]. FXR is thought to be the primary regulator of this steady-state process, inhibiting bile acid synthesis, while increasing bile acid secretion in hepatocytes and regulating bile acid content in the liver [3]. By modulating the FXR signal, bile acids themselves can act as signaling molecules that affect blood sugar and lipid metabolism [20].…”

Section: Discussionmentioning

confidence: 99%

“…Sterol 12 α -hydroxylase (CYP8B1) is an essential enzyme that promotes the synthesis of 12 α -hydroxylated bile acids [2]. Unlike CYP7A1, which is the rate-limiting enzyme of the classical pathway of bile acid metabolism, CYP8B1 is mainly responsible for the synthesis of 12 α -hydroxylated bile acids and controls the ratio of cholic acid in bile to that of chenodeoxycholic acid, among which cholic acid is the most abundant 12 α -hydroxylated bile acid in liver tissue [3]. Farnesol X receptor (FXR) is an activated transcriptional regulator of bile acid and glucose metabolism [4].…”

Section: Introductionmentioning

confidence: 99%

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A Possible Mechanism of Metformin in Improving Insulin Resistance in Diabetic Rat Models

et al. 2019

International Journal of Endocrinology

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Background Type 2 diabetes has become one of the most common diseases worldwide, causing a serious social burden. As a first-line treatment for diabetes, metformin can effectively improve insulin resistance. It has been reported that 12α-hydroxylated BA (mainly CA) is associated with insulin resistance. The purpose of this study was to analyze the changes in CA and possible signaling mechanisms in diabetic rats after metformin intervention. Methods HepG2 cells were cultured after adding different concentrations of metformin. The cell viability was measured using CCK8 kit, and the expression of FXR, MAFG, and CYP8B1 in cells was detected by WB. The rat models of type 2 diabetes were induced by low-dose streptozotocin by feeding a high-fat diet, and the control rats (CON) were fed on normal food; the diabetic rats (DM) were given a high-fat diet without supplementation with metformin, while the metformin-treated diabetic rats (DM + MET) were given a high-fat diet and supplemented with metformin. Biochemical parameters were detected at the end of the test. Expression levels of FXR, CYP8B1, and MAFG were assessed by WB. Serum CA were measured using an enzyme-linked immunosorbent assay (ELISA). Results In HepG2 cells, metformin dose-dependently enhanced the transcriptional activity of FXR and MAFG and inhibited the expression of CYP8B1. Metformin-treated DM rats showed improved glucose and bile acid metabolism. In addition, significantly increased FXR and MAFG and decreased CYP8B1 were observed in DM + MET rats. At the same time, the CA content of metformin-treated rats was lower than that of diabetic rats. Conclusion Changes in CA synthesis after metformin treatment may be associated with inhibition of CYP8B1. These results may play an important role in improving insulin sensitivity after metformin treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Possible Mechanism of Metformin in Improving Insulin Resistance in Diabetic Rat Models

et al. 2019

International Journal of Endocrinology

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“…Thus, estradiol treatment during late pregnancy was usually used to induce gestational cholestasis in animals. High estradiol exposure during late pregnancy could dysregulate bile acid homeostasis through inhibiting hepatic farnesoid X receptor (FXR) activity [17]. Ursodeoxycholic acid (UDCA) is a commonly used drug for the treatment of gestational cholestasis in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Obeticholic Acid Protects against Gestational Cholestasis-Induced Fetal Intrauterine Growth Restriction in Mice

Chen

Gao

et al. 2019

Oxidative Medicine and Cellular Longevity

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Gestational cholestasis is a common disease and is associated with adverse pregnancy outcomes. However, there are still no effective treatments. We investigated the effects of obeticholic acid (OCA) on fetal intrauterine growth restriction (IUGR) during 17α-ethynylestradiol- (E2-) induced gestational cholestasis in mice. All pregnant mice except controls were subcutaneously injected with E2 (0.625 mg/kg) daily from gestational day (GD) 13 to GD17. Some pregnant mice were orally administered with OCA (5 mg/kg) daily from GD12 to GD17. As expected, OCA activated placental, maternal, and fetal hepatic FXR signaling. Additionally, exposure with E2 during late pregnancy induced cholestasis, whereas OCA alleviated E2-induced cholestasis. Gestational cholestasis caused reduction of fetal weight and crown-rump length and elevated the incidence of IUGR. OCA decreased the incidence of IUGR during cholestasis. Interestingly, OCA attenuated reduction of blood sinusoid area in placental labyrinth layer and inhibited downregulation of placental sodium-coupled neutral amino acid transporter- (SNAT-) 2 during cholestasis. Additional experiment found that OCA attenuated glutathione depletion and lipid peroxidation in placenta and fetal liver and placental protein nitration during cholestasis. Moreover, OCA inhibited the upregulation of placental NADPH oxidase-4 and antioxidant genes during cholestasis. OCA activated antioxidant Nrf2 signaling during cholestasis. Overall, we demonstrated that OCA treatment protected against gestational cholestasis-induced placental dysfunction and IUGR through suppressing placental oxidative stress and maintaining bile acid homeostasis.

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“…Furthermore, reduced biliary secretion of BAs in ethinylestradiol-treated rats was coupled with unchanged fecal BA elimination. 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: Discussionmentioning

confidence: 99%

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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The ileum-liver Farnesoid X Receptor signaling axis mediates the compensatory mechanism of 17α-ethynylestradiol-induced cholestasis via increasing hepatic biosynthesis of chenodeoxycholic acids in rats

Cited by 13 publications

References 47 publications

A Possible Mechanism of Metformin in Improving Insulin Resistance in Diabetic Rat Models

A Possible Mechanism of Metformin in Improving Insulin Resistance in Diabetic Rat Models

Obeticholic Acid Protects against Gestational Cholestasis-Induced Fetal Intrauterine Growth Restriction in Mice

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

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