Hepatoprotection of auraptene from the peels of citrus fruits against 17α-ethinylestradiol-induced cholestasis in mice by activating farnesoid X receptor

Wang, Junqiao; Fu, Ting; Dong, Renchao; Wang, Changyuan; Liu, Kexin; Sun, Huijun; Huo, Xiaokui; Ma, Xiaodong; Yang, Xiaobo; Meng, Qiang

doi:10.1039/c9fo00318e

Cited by 24 publications

(8 citation statements)

References 37 publications

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“…Studies have shown that FXR could inhibit the bile acid synthase CYP7A1 and CYP8B1, promote the expression of bile acid e ux transporter, reduce the expression of bile acid uptake transporter [22][23][24]. In this study, the way of OCA improving cholestasis was mainly based on increasing bile acid e ux transporter to promote bile excretion.…”

Section: Discussionmentioning

confidence: 88%

Obeticholic Acid Protects Against Cholestatic Liver Injury Induced by Lithocholic Acid via Inhibiting Exogenous Cell Apoptosis

Zhu

Wang

et al. 2021

Preprint

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Background: Lithocholic acid (LCA) is one kind of endogenous bile acids which is a typical index in primary biliary cholangitis (PBC). It could cause severe cholestatic liver injury in rodents. Obeticholic acid (OCA) is a major treatment for PBC. However, its effect and mechanism in LCA-induced liver injury was still unclear beside of bile acid regulation. This study aims to evaluate the hepatoprotective effect and mechanism of OCA against LCA-induced cholestatic liver injury. Results: LCA-induced upregulations of ALT, AST, ALP and TBA were reduced and the bile acid profiles in serum, liver and bile were improved significantly by OCA. This bile acid regulating effect of OCA was mainly based on increasing the expression of bile acid efflux transporters bile salt export pump (BSEP), multidrug resistant associated protein 2 (MRP2), MRP3 and multi-drug resistance 3 (MDR3) instead of bile acid synthesis inhibition. Furthermore, it was found that OCA reduced the activation and expression of Caspase 8/3 signaling pathway without the change of p-MLKL and BAX in LCA-induced cholestatic model. And the inhibition of Caspase 8/3 signaling pathway depended on the activation of Farnesoid X receptor (FXR) to inhibit Caspase 8 cleavage to form a active complex.Conclusions: This study found OCA improved LCA-induced cholestatic liver injury via FXR-induced exogenous cell apoptosis, which provided a new evidence for the application of OCA to ameliorate PBC in clinical.

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Section: Discussionmentioning

confidence: 88%

Obeticholic Acid Protects Against Cholestatic Liver Injury Induced by Lithocholic Acid via Inhibiting Exogenous Cell Apoptosis

Zhu

Wang

et al. 2021

Preprint

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“…Studies have found that estrogens can increase the activity CYP7A1, CYP8B1 and CYP27A1, along with small transient increases in BA production ( Davis et al, 1986 ; Chico et al, 1996 ; Yang et al, 2020 ). In addition, estrogens can inhibit the expression of BA metabolic enzymes, especially phase II enzymes (such as hydroxysteroid sulfotransferase 2a1, Sult2a1), which in turn decreases the metabolism of bile acids, leading to an increased levels of unconjugated and hydrophobic bile acids in hepatocyte, and a decrease in bile flow ( Zamek-Gliszczynski et al, 2006 ; Zollner and Trauner, 2006 ; Wang et al, 2019 ).…”

Section: Pathophysiological Mechanisms Of Eicmentioning

confidence: 99%

“…As one of the most important BA sensors in maintaining BA homeostasis, nuclear receptor, farnasol X receptor (FXR) regulates the levels of hepatic transporters to affect BA homeostasis. Estrogens and their metabolites can inhibit the expression of FXR, which decreases the expression of BA transporters in the canalicular membranes of the liver ( Wang et al, 2019 ). This can cause retention of bile acids in hepatocytes and alters the compositions of BA, which subsequently leads to cholestatic liver injury ( Lee et al, 2000 ; Stieger et al, 2000 ).…”

Section: Pathophysiological Mechanisms Of Eicmentioning

confidence: 99%

The Pathological Mechanisms of Estrogen-Induced Cholestasis: Current Perspectives

Yang

Zhang

et al. 2021

Front. Pharmacol.

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Estrogens are steroid hormones with a wide range of biological activities. The excess of estrogens can lead to decreased bile flow, toxic bile acid (BA) accumulation, subsequently causing intrahepatic cholestasis. Estrogen-induced cholestasis (EIC) may have increased incidence during pregnancy, and within women taking oral contraception and postmenopausal hormone replacement therapy, and result in liver injury, preterm birth, meconium-stained amniotic fluid, and intrauterine fetal death in pregnant women. The main pathogenic mechanisms of EIC may include deregulation of BA synthetic or metabolic enzymes, and BA transporters. In addition, impaired cell membrane fluidity, inflammatory responses and change of hepatocyte tight junctions are also involved in the pathogenesis of EIC. In this article, we review the role of estrogens in intrahepatic cholestasis, and outlined the mechanisms of EIC, providing a greater understanding of this disease.

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“…Also the interaction of auraptene and the farnesoid X receptor, first put in evidence Epifano et al (2012), was further characterized studying the hepatoprotective action by auraptene against 17a-ethinylestradiol (EE)-induced cholestasis both in vitro using mice primary hepatocytes and in vivo in C57BL/6 mice (Wang et al 2019). These Authors first determined that compound (2) can modulate FXR target genes involved in the bile acid transport and synthesis.…”

Section: Auraptenementioning

confidence: 99%

Auraptene and umbelliprenin: a review on their latest literature acquisitions

et al. 2020

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Auraptene and umbelliprenin are among the most abundant naturally occurring prenyloxy umbelliferone derivatives. Both have been mainly isolated from plants belonging to numerous genera of the Rutaceae (in particular auraptene in Citrus spp.) and Apiaceae (in particular umbelliprenin in Ferula spp.) families, comprising different and widely used medicinal plants and in general plants having beneficial effects to human welfare as well as edible fruits and vegetables. Although known for quite a long time (nearly a century for auraptene and 50 years for umbelliprenin), only in the last two decades the two title natural compounds were revealed to possess valuable and promising pharmacological properties as dietary feeding active cancer chemopreventive, antibacterial, anti-protozoal, anti-fungal, anti-inflammatory, neuroprotective, and anti-oxidant agents among the activities best detailed in the recent literature. The aim of this comprehensive review is to outline in detail the effects described in the very last years for auraptene and umbelliprenin and what has been reported about the mechanisms of action underlying the observed pharmacological activities of these oxyprenylated secondary metabolites. In view of the herein described data suggestions on how to address the future research about both natural products in the best ways according to Authors will be also provided.

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Hepatoprotection of auraptene from the peels of citrus fruits against 17α-ethinylestradiol-induced cholestasis in mice by activating farnesoid X receptor

Abstract: Auraptene protects against estrogen-induced cholestasis in mice.

Cited by 24 publications

References 37 publications

Obeticholic Acid Protects Against Cholestatic Liver Injury Induced by Lithocholic Acid via Inhibiting Exogenous Cell Apoptosis

Obeticholic Acid Protects Against Cholestatic Liver Injury Induced by Lithocholic Acid via Inhibiting Exogenous Cell Apoptosis

The Pathological Mechanisms of Estrogen-Induced Cholestasis: Current Perspectives

Auraptene and umbelliprenin: a review on their latest literature acquisitions

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