Protective Role of Hydroxysteroid Sulfotransferase in Lithocholic Acid-induced Liver Toxicity

Kitada, Hirotaka; Miyata, Masaaki; Nakamura, Toshifumi; Tozawa, Aki; Honma, Wataru; Shimada, M.; Nagata, Kiyoshi; Sinal, Christopher J.; Guo, Grace L.; Gonzalez, Frank J.; Yamazoe, Yasushi

doi:10.1074/jbc.m210634200

Cited by 148 publications

(158 citation statements)

References 45 publications

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“…8,9 A subsequent study suggested that Mrp4 was not elevated upon feeding the hydrophobic bile acid, lithocholic acid. 10 Despite this finding, other studies have demonstrated that hepatic Mrp4 is upregulated in both rats and mice after bile duct ligation 6,11 and in pediatric patients with progressive familial intrahepatic cholestasis. 12 Recent studies demonstrate that MRP4 functions as an efflux pump for bile acids together with glutathione.…”

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confidence: 53%

Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

et al. 2006

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Mrp4 is a member of the multidrug resistance-associated gene family that is expressed on the basolateral membrane of hepatocytes and undergoes adaptive upregulation in response to cholestatic injury or bile acid feeding. However, the relative importance of Mrp4 in a protective adaptive response to cholestatic injury is not known. To address this issue, common bile duct ligation (CBDL) was performed in wild-type and Mrp4؊/؊ mice and animals followed for 7 days. Histological analysis and serum aminotransferase levels revealed more severe liver injury in the absence of Mrp4 expression. Western analyses revealed that Mrp4, but not Mrp3, was significantly increased after CBDL in wild-type mice. Serum bile acid levels were significantly lower in Mrp4؊/؊ mice than in wild-type CBDL mice, whereas serum bilirubin levels were the same, suggesting that Mrp4 was required to effectively extrude bile acids from the cholestatic liver. Mrp3 and Ost␣-Ost␤ were upregulated in Mrp4؊/؊ mice but were unable to compensate for the loss of Mrp4. High-performance liquid chromatography analysis on liver extracts revealed that taurine tetrahydroxy bile acid/beta-muricholic acid ratios were increased twofold in Mrp4؊/؊ mice. In conclusion, hepatic Mrp4 plays a unique and essential protective role in the adaptive response to obstructive cholestatic liver injury. ( M ultidrug resistance-associated protein 4 (MRP4) (ABCC4) is an ATP-dependent organic anion transporter with broad substrate specificity. [1][2][3] It is a member of the ABC transporter superfamily 4 and is expressed in a variety of epithelia, including the basolateral and apical plasma membranes of the liver and kidneys, respectively. 5-7 However, this array of substrates and specific tissue localization have not provided insight into Mrp4 function in vivo.Mrp4 was first suggested to play a role in the adaptive response to the hepatic overload of bile acids following the genetic deletion of farnesoid X receptor (FXR), a bile acid sensor. 8,9 A subsequent study suggested that Mrp4 was not elevated upon feeding the hydrophobic bile acid, lithocholic acid. 10 Despite this finding, other studies have demonstrated that hepatic Mrp4 is upregulated in both rats and mice after bile duct ligation 6,11 and in pediatric patients with progressive familial intrahepatic cholestasis. 12 Recent studies demonstrate that MRP4 functions as an efflux pump for bile acids together with glutathione. 13 Further support for a role for MRP4 in hepatic bile acid overload is the recent demonstration that Mrp4 is upregulated by the constitutive androstane receptor. 14 Constitutive androstane receptor is a member of the nuclear hormone receptor superfamily that is required to elevate serum bile acids during cholestatic injury. 15 Cholestatic injury in mice, rats, and humans can also result in adaptive responses in other basolateral transporters. Examples include Mrp3, which is primarily a bilirubin conjugate transporter and also a constitutive androstane receptor target, 15 and the recently described heterodi...

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confidence: 53%

Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

et al. 2006

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“…As shown in previous studies (11,25), Fxr Ϫ/Ϫ mice exhibited increased basal bile acid levels. Importantly, levels of bile acids and ALP activity were further increased by EE2 in Fxr Ϫ/Ϫ mice, suggesting that EE2 treatment induced hepatotoxicity via an FXR-independent mechanism.…”

Section: Lack Of Ee2-induced Hepatotoxicity In Er␣-null Mice-to Studymentioning

confidence: 80%

Estrogen Receptor α Mediates 17α-Ethynylestradiol Causing Hepatotoxicity

Yamamoto

Moore

Hess

et al. 2006

Journal of Biological Chemistry

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155

114

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Estrogens are known to cause hepatotoxicity such as intrahepatic cholestasis in susceptible women during pregnancy, after administration of oral contraceptives, or during postmenopausal replacement therapy. Enterohepatic nuclear receptors including farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive active/androstane receptor (CAR) are important in maintaining bile acid homeostasis and protecting the liver from bile acid toxicity. However, no nuclear receptor has been implicated in the mechanism for estrogen-induced hepatotoxicity. Here Era

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“…It therefore seems likely that the hepatic Cyp3a11 induction that we have demonstrated mediates the increase in bile acid 6␤-hydroxylation. However, recent work has demonstrated an increase in Cyp3a11 in LCAfed, FXR-null mice, associated with a decrease in LCA 6␤-hydroxylation, an increase in LCA 6␣-hydroxylation and an increase in testosterone 6␤-hydroxylation (35). This suggests that in mice, several enzymes may mediate stereospecific hydroxylase reactions of different bile acid and steroid substrates.…”

Section: Discussionmentioning

confidence: 96%

Feed-forward Regulation of Bile Acid Detoxification by CYP3A4

Stedman

Robertson

Coulter

et al. 2004

Journal of Biological Chemistry

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Bile acids are potentially toxic end products of cholesterol metabolism and their concentrations must be tightly regulated. Homeostasis is maintained by both feed-forward regulation and feedback regulation. We used humanized transgenic mice incorporating 13 kb of the 5 regulatory flanking sequence of CYP3A4 linked to a lacZ reporter gene to explore the in vivo relationship between bile acids and physiological adaptive CYP3A gene regulation in acute cholestasis after bile duct ligation (BDL). Male transgenic mice were subjected to BDL or sham surgery prior to sacrifice on days 3, 6, and 10, and others were injected with intraperitoneal lithocholic acid (LCA) or vehicle alone. BDL resulted in marked hepatic activation of the CYP3A4/lacZ transgene in pericentral hepatocytes, with an 80-fold increase in transgene activation by day 10. Individual bile acids were quantified by liquid chromatography/mass spectrometry. Serum 6␤-hydroxylated bile acids were increased following BDL, confirming the physiological relevance of endogenous Cyp3a induction to bile acid detoxification. Although concentrations of conjugated primary bile acids increased after BDL, there was no increase in LCA, a putative PXR ligand, indicating that this cannot be the only endogenous bile acid mediating this protective response. Moreover, in LCA-treated animals, 5-bromo-4-chloro-3-indolyl-␤-D-galactopyranoside staining showed hepatic activation of the CYP3A4 transgene only on the liver capsular surface, and minimal parenchymal induction, despite significant liver injury. This study demonstrates that CYP3A up-regulation is a significant in vivo adaptive response to cholestasis. However, this up-regulation is not dependent on increases in circulating LCA and the role of other bile acids as regulatory molecules requires further exploration.

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Protective Role of Hydroxysteroid Sulfotransferase in Lithocholic Acid-induced Liver Toxicity

Cited by 148 publications

References 45 publications

Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

Estrogen Receptor α Mediates 17α-Ethynylestradiol Causing Hepatotoxicity

Feed-forward Regulation of Bile Acid Detoxification by CYP3A4

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