Farnesoid X receptor, hepatocyte nuclear factors 1α and 3β are essential for transcriptional activation of the liver-specific organic anion transporter-2 gene

Background: Total parenteral nutrition (TPN) provides all nutritional needs intravenously. Although lifesaving, enthusiasm is significantly tempered due to side effects of liver and gut injury, as well as lack of mechanistic understanding into drivers of TPN injury. We hypothesized that the state of luminal nutritional deprivation with TPN drives alterations in gut–systemic signaling, contributing to injury, and tested this hypothesis using our ambulatory TPN model. Methods: A total of 16 one-week-old piglets were allocated randomly to TPN (n = 8) or enteral nutrition (EN, n = 8) for 3 weeks. Liver, gut, and serum were analyzed. All tests were two-sided, with a significance level of 0.05. Results: TPN resulted in significant hyperbilirubinemia and cholestatic liver injury, p = 0.034. Hepatic inflammation (cluster of differentiation 3 (CD3) immunohistochemistry) was higher with TPN (p = 0.021). No significant differences in alanine aminotransferase (ALT) or bile ductular proliferation were noted. TPN resulted in reduction of muscularis mucosa thickness and marked gut atrophy. Median and interquartile range for gut mass was 0.46 (0.30–0.58) g/cm in EN, and 0.19 (0.11–0.29) g/cm in TPN (p = 0.024). Key gut–systemic signaling regulators, liver farnesoid X receptor (FXR; p = 0.021), liver constitutive androstane receptor (CAR; p = 0.014), gut FXR (p = 0.028), G-coupled bile acid receptor (TGR5) (p = 0.003), epidermal growth factor (EGF; p = 0.016), organic anion transporter (OAT; p = 0.028), Mitogen-activated protein kinases-1 (MAPK1) (p = 0.037), and sodium uptake transporter sodium glucose-linked transporter (SGLT-1; p = 0.010) were significantly downregulated in TPN animals, whereas liver cholesterol 7 alpha-hydroxylase (CyP7A1) was substantially higher with TPN (p = 0.011). Conclusion: We report significant alterations in key hepatobiliary receptors driving gut–systemic signaling in a TPN piglet model. This presents a major advancement to our understanding of TPN-associated injury and suggests opportunities for strategic targeting of the gut–systemic axis, specifically, FXR, TGR5, and EGF in developing ameliorative strategies.

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Reabsorption of bile acids regulated by FXR-OATP1A2 is the main factor for the formation of cholesterol gallstone

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00385.2019 ◽

2020 ◽

Vol 319 (3) ◽

pp. G303-G308

Author(s):

Jingli Cai ◽

Zhaowen Wang ◽

Guiming Chen ◽

Dapeng Li ◽

Jun Liu ◽

...

Keyword(s):

Bile Acids ◽

Cholesterol Gallstone ◽

Organic Anion ◽

Farnesoid X Receptor ◽

Organic Anion Transporter ◽

Anion Transporter ◽

First Time ◽

Main Factor

For the first time, our results indicate that the axis of farnesoid X receptor-organic anion transporter polypeptide 1A2 that physiologically regulates the reabsorption of bile acids might play an important role in the regulation of the composition of bile acids and make contribution to the development of cholelithiasis.

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OATP1B3-1B7, a novel organic anion transporting polypeptide, is modulated by FXR ligands and transports bile acids

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00330.2018 ◽

2019 ◽

Vol 317 (6) ◽

pp. G751-G762 ◽

Cited By ~ 1

Author(s):

Vanessa Malagnino ◽

Janine Hussner ◽

Ali Issa ◽

Angela Midzic ◽

Henriette E. Meyer zu Schwabedissen

Keyword(s):

Endoplasmic Reticulum ◽

Bile Acid ◽

Bile Acids ◽

Smooth Endoplasmic Reticulum ◽

Organic Anion ◽

Farnesoid X Receptor ◽

Organic Anion Transporter ◽

Organic Anion Transporting Polypeptide ◽

Anion Transporter ◽

Solute Carrier

Organic anion transporting polypeptide (OATP) 1B3–1B7 (LST-3TM12) is a member of the OATP1B [solute carrier organic anion transporter ( SLCO) 1B] family. This transporter is not only functional but also expressed in the membrane of the smooth endoplasmic reticulum of hepatocytes and enterocytes. OATP1B3–1B7 is a splice variant of SLCO1B3 in which the initial part is encoded by SLCO1B3, whereas the rest of the mRNA originates from the gene locus of SLCO1B7. In this study, we not only showed that SLCO1B3 and the mRNA encoding for OATP1B3–1B7 share the 5′ untranslated region but also that silencing of an initial SLCO1B3 exon lowered the amount of SLCO1B3 and of SLCO1B7 mRNA in Huh-7 cells. To validate the assumption that both transcripts are regulated by the same promoter we tested the influence of the bile acid sensor farnesoid X receptor (FXR) on their transcription. Treatment of Huh-7 and HepaRG cells with activators of this known regulator of OATP1B3 not only increased SLCO1B3 but also OATP1B3–1B7 mRNA transcription. Applying a heterologous expression system, we showed that several bile acids interact with OATP1B3–1B7 and that taurocholic acid and lithocholic acid are OATP1B3–1B7 substrates. As OATP1B3–1B7 is located in the smooth endoplasmic reticulum, it may grant access to metabolizing enzymes. In accordance are our findings showing that the OATP1B3–1B7 inhibitor bromsulphthalein significantly reduced uptake of bile acids into human liver microsomes. Taken together, we report that OATP1B3–1B7 transcription can be modulated with FXR agonists and antagonists and that OATP1B3–1B7 transports bile acids. NEW & NOTEWORTHY Our study on the transcriptional regulation of the novel organic anion transporting polypeptide (OATP) 1B3–1B7 concludes that the promoter of solute carrier organic anion transporter ( SLCO) 1B3 governs SLCO1B3–1B7 transcription. Moreover, the transcription of OATP1B3–1B7 can be modulated by farnesoid X receptor (FXR) agonists and antagonists. FXR is a major regulator in bile acid homeostasis that links OATP1B3–1B7 to this physiological function. Findings in transport studies with OATP1B3–1B7 suggest that this transporter interacts with the herein tested bile acids.

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Dexamethasone induces an imbalanced fetal-placental-maternal bile acid circulation: involvement of placental transporters

BMC Medicine ◽

10.1186/s12916-021-01957-y ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Wen Huang ◽

Jin Zhou ◽

Juanjuan Guo ◽

Wen Hu ◽

Guanghui Chen ◽

...

Keyword(s):

Bile Acid ◽

Organic Anion ◽

Maternal Serum ◽

Farnesoid X Receptor ◽

Organic Anion Transporter ◽

Cancer Resistance ◽

Rat Serum ◽

Altered Expression ◽

Anion Transporter ◽

Fetal Serum

Abstract Background The use of prenatal dexamethasone remains controversial. Our recent studies found that prenatal dexamethasone exposure can induce maternal intrahepatic cholestasis and have a lasting adverse influence on bile acid (BA) metabolism in the offspring. The purpose of this study was to investigate the effects of dexamethasone on fetal-placental-maternal BA circulation during the intrauterine period, as well as its placental mechanism. Methods Clinical data and human placentas were collected and analyzed. Pregnant Wistar rats were injected subcutaneously with dexamethasone (0.2 mg/kg per day) from gestational day 9 to 20. The metabolomic spectra of BAs in maternal and fetal rat serum were determined by LC-MS. Human and rat placentas were collected for histological and gene expression analysis. BeWo human placental cell line was treated with dexamethasone (20–500 nM). Results Human male neonates born after prenatal dexamethasone treatment showed an increased serum BA level while no significant change was observed in females. Moreover, the expression of organic anion transporter polypeptide-related protein 2B1 (OATP2B1) and breast cancer resistance protein (BCRP) in the male neonates’ placenta was decreased, while multidrug resistance-associated protein 4 (MRP4) was upregulated. In experimental rats, dexamethasone increased male but decreased female fetal serum total bile acid (TBA) level. LC-MS revealed that primary BAs were the major component that increased in both male and female fetal serum, and all kinds of BAs were significantly increased in maternal serum. The expression of Oatp2b1 and Bcrp were reduced, while Mrp4 expression was increased in the dexamethasone-treated rat placentas. Moreover, dexamethasone increased glucocorticoid receptor (GR) expression and decreased farnesoid X receptor (FXR) expression in the rat placenta. In BeWo cells, dexamethasone induced GR translocation into the nucleus; decreased FXR, OATP2B1, and BCRP expression; and increased MRP4 expression. Furthermore, GR was verified to mediate the downregulation of OATP2B1, while FXR mediated dexamethasone-altered expression of BCRP and MRP4. Conclusions By affecting placental BA transporters, dexamethasone induces an imbalanced fetal-placental-maternal BA circulation, as showed by the increase of primary BA levels in the fetal serum. This study provides an important experimental and theoretical basis for elucidating the mechanism of dexamethasone-induced alteration of maternal and fetal BA metabolism and for exploring early prevention and treatment strategies.

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The transcriptional activation of liver-specific organic anion transporter-2 gene is regulated by three liver enriched transcriptional factors; Hnfla, Hnf3b, and Fxr

Gastroenterology ◽

10.1016/s0016-5085(03)83670-3 ◽

2003 ◽

Vol 124 (4) ◽

pp. A726-A727

Author(s):

Hideo Ohtsuka ◽

Michiaki Unno ◽

Takaaki Abe ◽

Yu Katayose ◽

Toshiki Rikiyama ◽

...

Keyword(s):

Transcriptional Activation ◽

Organic Anion ◽

Transcriptional Factors ◽

Organic Anion Transporter ◽

Anion Transporter

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Cytokine-dependent regulation of hepatic organic anion transporter gene transactivators in mouse liver

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00307.2004 ◽

2005 ◽

Vol 289 (5) ◽

pp. G831-G841 ◽

Cited By ~ 70

Author(s):

Andreas Geier ◽

Christoph G. Dietrich ◽

Sebastian Voigt ◽

Meenakshisundaram Ananthanarayanan ◽

Frank Lammert ◽

...

Keyword(s):

Mrna Expression ◽

Hormone Receptors ◽

Organic Anion ◽

Pregnane X Receptor ◽

Regulatory Elements ◽

Farnesoid X Receptor ◽

Organic Anion Transporter ◽

Mrna Levels ◽

Anion Transporter ◽

Tnf Α

Proinflammatory cytokines such as TNF-α and IL-1β lead to downregulation of hepatic organic anion transporters in cholestasis. This adapted response is transcriptionally mediated by nuclear hormone receptors and liver-specific transcription factors. Because little is known in vivo about cytokine-dependent regulatory events, mice were treated with either TNF-α or IL-1β for up to 16 h. Transporter mRNA expression was determined by Northern blot analysis, nuclear activity, and protein-expression of transactivators by EMSA and Western blotting. TNF-α induces a sustained decrease in Ntcp, Oatp1/Oatp1a1, and Bsep mRNA expression but exerts only transient [multidrug resistance-associated protein 2 (Mrp2)] or no effects (Mrp3) on Mrps. In addition to Ntcp and Oatp1/Oatp1a1, IL-1β also downregulates Bsep, Mrp2, and Mrp3 mRNAs to some extent. To study transcriptional regulation, Ntcp and Bsep promoters were first cloned from mice revealing a new distal Ntcp hepatocyte nuclear factor 1 (HNF-1) element but otherwise show a conserved localization to known rat regulatory elements. Changes in transporter-expression are preceeded by a reduction in binding activities at IR-1, ER-8, DR-5, and HNF-1α sites after 4 h by either cytokine, which remained more sustained by TNF-α in the case of nuclear receptors. Nuclear protein levels of retinoid X receptor (RXR)-α are significantly decreased by TNF-α but only transiently affected by IL-1β. Minor reductions of retinoic acid receptor, farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor nuclear proteins are restricted to 4 h after cytokine application and paralleled by a decrease in mRNA levels. Basolateral and canalicular transporter systems are downregulated by both cytokines, TNF-α and IL-1β. Activity of HNF-1α as regulator of mNtcp is suppressed by both cytokines. Decreased binding activities of nuclear receptor heterodimers may be explained by a reduction of the ubiquitous heterodimerization partner RXR-α.

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