Elevated hepatic multidrug resistance-associated protein 3/ATP-binding cassette subfamily C 3 expression in human obstructive cholestasis is mediated through tumor necrosis factor alpha and c-Jun NH2-terminal kinase/stress-activated protein kinase–signaling pathway

Chai, Jin; He, Yu; Cai, Shi‐Ying; Jiang, Zhongyong; Wang, Huaizhi; Li, Qiong; Chen, Lei; Peng, Zhihong; He, Xiaofu; Wu, Xiaoping; Xiao, Tao; Wang, Rongquan; Boyer, James L.; Chen, Wensheng

doi:10.1002/hep.24801

Cited by 75 publications

(99 citation statements)

References 31 publications

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“…To identify mechanisms by which disruption of Vhl repress CYP7A1 expression, several known pathways important in the regulation of CYP7A1 were assessed. Activation of JNK induces hypercholesterolemia and cholestasis (38) and is a potent inhibitor of Cyp7a1 expression (39). Consistent with inflammation in the livers of Vhl LivKO mice (9), JNK phosphorylation was significantly increased at 5 days and 2 weeks after disruption of Vhl (Fig.…”

Section: Disruption Of Hepatic Vhl Results In Hypercholesterolemiasupporting

confidence: 58%

Loss of von Hippel-Lindau Protein (VHL) Increases Systemic Cholesterol Levels through Targeting Hypoxia-Inducible Factor 2α and Regulation of Bile Acid Homeostasis

Ramakrishnan

Taylor

et al. 2014

Molecular and Cellular Biology

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Cholesterol synthesis is a highly oxygen-dependent process. Paradoxically, hypoxia is correlated with an increase in cellular and systemic cholesterol levels and risk of cardiovascular diseases. The mechanism for the increase in cholesterol during hypoxia is unclear. Hypoxia signaling is mediated through hypoxia-inducible factor 1␣ (HIF-1␣) and HIF-2␣. The present study demonstrates that activation of HIF signaling in the liver increases hepatic and systemic cholesterol levels due to a decrease in the expression of cholesterol hydroxylase CYP7A1 and other enzymes involved in bile acid synthesis. Specifically, activation of hepatic HIF-2␣ (but not HIF-1␣) led to hypercholesterolemia. HIF-2␣ repressed the circadian expression of Rev-erb␣, resulting in increased expression of E4BP4, a negative regulator of Cyp7a1. To understand if HIF-mediated decrease in bile acid synthesis is a physiologically relevant pathway by which hypoxia maintains or increases systemic cholesterol levels, two hypoxic mouse models were assessed, an acute lung injury model and mice exposed to 10% O 2 for 3 weeks. In both models, cholesterol levels increased with a concomitant decrease in expression of genes involved in bile acid synthesis. The present study demonstrates that hypoxic activation of hepatic HIF-2␣ leads to an adaptive increase in cholesterol levels through inhibition of bile acid synthesis. Cholesterol is an essential nutrient important in many metabolic processes, and its levels are tightly regulated. Cholesterol synthesis is a highly oxygen-dependent process. The final step from lanosterol to cholesterol conversion requires nine molecules of dioxygen (1). However, systemic hypoxia is associated with an increase in cholesterol levels. Individuals living at high altitude are at high risk for coronary heart disease due to elevated low-density lipoprotein and total cholesterol levels caused by high-altitude hypoxia (2). In chronic hypoxic diseases, such as in patients with obstructive sleep apnea, no change or an increase in serum and liver cholesterol levels are observed, which can be reversed by continuous positive airway pressure (3-5). Moreover, mice exposed to chronic intermittent hypoxia (CIH) have a significant increase in total cholesterol levels (6, 7). These studies suggest that hypoxiasignaling pathways activate an adaptive response important in cholesterol homeostasis. Several mechanisms were proposed to account for hypoxia-induced dyslipidemia (8, 9). However, the mechanisms by which hypoxia regulates cholesterol homeostasis are not clear. Hypoxic signaling is mediated by an oxygen-sensitive transcription factor, hypoxia-inducible factor (HIF), consisting of two isoforms, HIF-1␣ and HIF-2␣ (10). Activation of HIF-1␣ induces glycolytic genes, whereas activation of HIF-2␣ regulates the expression of genes that are involved in fatty acid synthesis, fatty acid uptake, inflammation, fibrosis, and vascular tumors (9,(11)(12)(13)(14).In this study, liver hypoxia-induced dyslipidemia was shown to be associated with spontaneou...

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Section: Disruption Of Hepatic Vhl Results In Hypercholesterolemiasupporting

confidence: 58%

Loss of von Hippel-Lindau Protein (VHL) Increases Systemic Cholesterol Levels through Targeting Hypoxia-Inducible Factor 2α and Regulation of Bile Acid Homeostasis

Ramakrishnan

Taylor

et al. 2014

Molecular and Cellular Biology

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“…PXR and CAR are, however, also activated by hydrophobic bile acids (PXR) and bilirubin (indirect activation; CAR) in rodent and human hepatocytes (Staudinger et al, 2001;Xie et al, 2001;Huang et al, 2003b). This activation induces hepatocellular bile acid excretion (ABCC2, ABCC3, ABCC4) and detoxification (CYP3A4/CYP2B10/SULT2A1) (Xie et al, 2000;Marschall et al, 2005;Chai et al, 2011Chai et al, , 2012 and stimulates bilirubin conjugation (UGT1A1) and excretion (ABCC2) (Huang et al, 2003b;Marschall et al, 2005). PXR also represses bile acid synthesis (via CYP7A1) (Staudinger et al, 2001).…”

Section: Bile Acid Metabolism and Its Regulationmentioning

confidence: 99%

The Role of Canalicular ABC Transporters in Cholestasis

et al. 2014

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Cholestasis, a hallmark feature of hepatobiliary disease, is characterized by the retention of biliary constituents. Some of these constituents, such as bile acids, inflict damage to hepatocytes and bile duct cells. This damage may lead to inflammation, fibrosis, cirrhosis, and eventually carcinogenesis, sequelae that aggravate the underlying disease and deteriorate clinical outcome. Canalicular ATP-binding cassette (ABC) transporters, which mediate the excretion of individual bile constituents, play a key role in bile formation and cholestasis. The study of these transporters and their regulatory nuclear receptors has revolutionized our understanding of cholestatic disease. This knowledge has served as a template to develop novel treatment strategies, some of which are currently already undergoing phase III clinical trials. In this review we aim to provide an overview of the structure, function, and regulation of canalicular ABC transporters. In addition, we will focus on the role of these transporters in the pathogenesis and treatment of cholestatic bile duct and liver diseases.

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“…Under normal physiologic conditions, the hepatic expression of MRP3 and MRP4 is low, whereas upregulation under cholestatic conditions (e.g., inhibition of BSEP, genetic BSEP variants) has been observed (Gradhand et al, 2008;Chai et al, 2012). Therefore, these basolateral proteins are hypothesized to provide a compensatory backup system for bile acid efflux from the hepatocyte into sinusoidal blood when the normal vectorial transport of bile acids from the hepatocyte into bile is compromised (Scheffer et al, 2002;Teng and Piquette-Miller, 2007;Gradhand et al, 2008;Chai et al, 2012). The contribution of Mrp4 to bile acid homeostasis and its role in the development of liver injury are highlighted by elevated liver concentrations of specific bile acids and increased liver toxicity in bile duct-ligated Mrp4 knockout compared with wild-type mice (Mennone et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Risk Factors for Development of Cholestatic Drug-Induced Liver Injury: Inhibition of Hepatic Basolateral Bile Acid Transporters Multidrug Resistance-Associated Proteins 3 and 4

et al. 2013

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Impaired hepatic bile acid export may contribute to development of cholestatic drug-induced liver injury (DILI). The multidrug resistance-associated proteins (MRP) 3 and 4 are postulated to be compensatory hepatic basolateral bile acid efflux transporters when biliary excretion by the bile salt export pump (BSEP) is impaired. BSEP inhibition is a risk factor for cholestatic DILI. This study aimed to characterize the relationship between MRP3, MRP4, and BSEP inhibition and cholestatic potential of drugs. The inhibitory effect of 88 drugs (100 mM) on MRP3-and MRP4-mediated substrate transport was measured in membrane vesicles. Drugs selected for investigation included 50 BSEP non-inhibitors (24 non-cholestatic; 26 cholestatic) and 38 BSEP inhibitors (16 noncholestatic; 22 cholestatic). MRP4 inhibition was associated with an increased risk of cholestatic potential among BSEP non-inhibitors. In this group, for each 1% increase in MRP4 inhibition, the odds of the drug being cholestatic increased by 3.1%. Using an inhibition cutoff of 21%, which predicted a 50% chance of cholestasis, 62% of cholestatic drugs inhibited MRP4 (P < 0.05); in contrast, only 17% of non-cholestatic drugs were MRP4 inhibitors. Among BSEP inhibitors, MRP4 inhibition did not provide additional predictive value of cholestatic potential; almost all BSEP inhibitors were also MRP4 inhibitors. Inclusion of pharmacokinetic predictor variables (e.g., maximal unbound concentration in plasma) in addition to percent MRP4 inhibition in logistic regression models did not improve cholestasis prediction. Association of cholestasis with percent MRP3 inhibition was not statistically significant, regardless of BSEP-inhibition status. Inhibition of MRP4, in addition to BSEP, may be a risk factor for the development of cholestatic DILI.

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Elevated hepatic multidrug resistance-associated protein 3/ATP-binding cassette subfamily C 3 expression in human obstructive cholestasis is mediated through tumor necrosis factor alpha and c-Jun NH2-terminal kinase/stress-activated protein kinase–signaling pathway

Cited by 75 publications

References 31 publications

Loss of von Hippel-Lindau Protein (VHL) Increases Systemic Cholesterol Levels through Targeting Hypoxia-Inducible Factor 2α and Regulation of Bile Acid Homeostasis

Loss of von Hippel-Lindau Protein (VHL) Increases Systemic Cholesterol Levels through Targeting Hypoxia-Inducible Factor 2α and Regulation of Bile Acid Homeostasis

The Role of Canalicular ABC Transporters in Cholestasis

Risk Factors for Development of Cholestatic Drug-Induced Liver Injury: Inhibition of Hepatic Basolateral Bile Acid Transporters Multidrug Resistance-Associated Proteins 3 and 4

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