Abcb11 Deficiency Induces Cholestasis Coupled to Impaired β-Fatty Acid Oxidation in Mice

Zhang, Yuanyuan; Li, Fēi; Patterson, Andrew D.; Wang, Yao; Krausz, Kristopher W.; Neale, Geoffrey; Thomas, Sarah; Nachagari, Deepa; Vogel, Peter; Vore, Mary; Gonzalez, Frank J.; Schuetz, John D.

doi:10.1074/jbc.m111.329318

Cited by 75 publications

(70 citation statements)

References 55 publications

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“…In mice, the defect in bile acid export from the hepatocyte is easily shown by feeding such mice cholic acid ( 278 ), which in this condition is highly toxic. Impaired ␤ -fatty acid oxidation is also present in in such cholic acidfed animals ( 279 ). circulation of bile acids with values for man was presented by Sune Bergström in 1959 ( 8 ) and is shown in Fig.…”

Section: Imaging Of Bile Acid Transport An 11mentioning

confidence: 95%

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

Hofmann

Hagey

2014

Journal of Lipid Research

304

284

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conceptions are rare, and provocative judgments stand the test of time. Let us also hope that this effort will be both useful and entertaining. Each of the topics discussed merits at least a full length article, so there will be, of necessity in many instances, consideration of only what we perceive to be the highlights. THE EBB AND FLOW OF MEDICAL INTEREST IN BILE ACIDSAfter the elucidation of the true chemical structure of bile acids in 1932 (see below), there was little interest in bile acids in the Western world. One exception to this statement was the laboratory of Siegfried Thannhauser, who wrote the fi rst textbook of metabolic biochemistry in Germany. He studied cholesterol and bile acid balance in the biliary fi stula dog ( 1 ). During this time, bile acids were sold as liver tonics and laxatives, but there were no placebo-controlled studies showing effi cacy. Indeed, bile acids were considered by the medical profession to have no useful therapeutic properties. The tri-oxo derivative of cholic acid (called "dehydrocholic acid") was known to induce bile fl ow in animals ( 2 ), and was occasionally used to stimulate bile fl ow in patients; but again there were no controlled studies showing effi cacy in hepatobiliary disease.

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Section: Imaging Of Bile Acid Transport An 11mentioning

confidence: 95%

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

Hofmann

Hagey

2014

Journal of Lipid Research

304

284

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“…The elevated levels of serum triglycerides are consistent with the reduction in expression levels of hepatic genes encoding the enzymes CPT2, ACOT1, ACOT2, MCAD, and the receptor CD36. Levels of urinary DHOPA regulated by 21-hydroxysteroid dehydrogenase can be elevated in other pathological conditions in which fatty acid oxidation is inhibited (3,35). In addition, liver inflammation might have resulted in the activation of phospholipid metabolism.…”

Section: Fig 4 Hepatic Levels Of Metabolites and Gene Expression Inmentioning

confidence: 99%

Metabolomics Reveals That Tumor Xenografts Induce Liver Dysfunction

Patterson

Krausz

et al. 2013

Molecular & Cellular Proteomics

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Metabolomics, based on ultraperformance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry, was used to explore metabolic signatures of tumor growth in mice. Urine samples were collected from control mice and mice injected with squamous cell carcinoma (SCCVII) tumor cells. When tumors reached ϳ2 cm, all mice were killed and blood and liver samples collected. The urine metabolites hexanoylglycine, nicotinamide 1-oxide, and 11␤,20␣-dihydroxy-3-oxopregn-4-en-21-oic acid were elevated in tumor-bearing mice, as was asymmetric dimethylarginine, a biomarker for oxidative stress. Interestingly, SCCVII tumor growth resulted in hepatomegaly, reduced albumin/globulin ratios, and elevated serum triglycerides, suggesting liver dysfunction. Alterations in liver metabolites between SCCVII-tumor-bearing and control mice confirmed the presence of liver injury. Hepatic mRNA analysis indicated that inflammatory cytokines, tumor necrosis factor ␣, and transforming growth factor ␤ were enhanced in SCCVII-tumor-bearing mice, and the expression of cytochromes P450 was decreased in tumor-bearing mice. Further, genes involved in fatty acid oxidation were decreased, suggesting impaired fatty acid oxidation in SCCVII-tumor-bearing mice. Additionally, activated phospholipid metabolism and a disrupted tricarboxylic acid cycle were observed in SCCVIItumor-bearing mice. These data suggest that tumor growth imposes a global inflammatory response that results in liver dysfunction and underscore the use of metabolomics to temporally examine these changes and potentially use metabolite changes to monitor tumor treatment response. The combination of nuclear magnetic resonance and liquid and gas chromatography coupled to mass spectrometry has enabled the global analysis of metabolites in small volumes of biofluids and tissues. Using this technology, the emerging field of metabolomics seeks to elucidate how pathological conditions, genetic modifications, and xenobiotic exposure can lead to alterations in biochemical pathways of an organism as measured via metabolite profile analysis (1-4). The applications of this technology extend beyond those mentioned above (5) and further hold promise for identifying biomarkers that might provide early diagnostic information characterizing a variety of disease processes. Such biomarkers might also be most useful for following the course of therapy and perhaps predicting treatment outcomes.Cancer is a disease amenable to metabolite interrogation, as many human tumors are difficult to detect at an early stage of development, when they are most vulnerable to treatment. Moreover, many human tumors are unresponsive to a wide variety of therapies, and metabolite profile anomalies specific to cancer might provide targets or pathways for the development of new treatment strategies. A number of different types of human cancers have been subjected to metabolomic analysis (5), and specific metabolites were identified that may provide diagnostic information. Examples include urine sarcos...

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“…These two factors, reducing the toxicity of accumulated bile acids through hydroxylation and canalicular secretion of the polyhydroxy bile acids by an alternative transport system, resulted in a mild phenotype in the abcb11 Ϫ/Ϫ mice compared with their human genetic disease equivalent, PFIC2. A recent report by Zhang et al (42) suggests that other factors, such as deficiency in ␤-oxidation of fatty acids, may contribute to the more progressive cholestatic phenotype observed in their strain of abcb11 Ϫ/Ϫ mice, developed on a pure C57Bl/6 genetic background.…”

Section: (Oh) T (Oh)2 T (Oh)3 T (Oh)4 T (Oh)5 (Ohmentioning

confidence: 99%

“…We have not identified the exact chemical nature of the tetrahydroxy and pentahydroxy bile acids that were produced in the livers of abcb11 Ϫ/Ϫ mice. Based on the findings of Perwaiz et al (27), Zhang et al (42), and Zollner (43), the tetrahydroxy bile acids are likely to be formed by hydroxylation at C-12 and C-6 of UDCA (and its conjugates) to form 12␣-hydroxy-␤-muricholic acid (3␣,6␤,7␤,12␣) and 12␣-hydroxy--muricholic acid (3␣,6␣,7␤,12␣). While this work was in progress, Zhang et al (42), reported the presence of 2␤-hydroxy-cholic acid in abcb11 Ϫ/Ϫ mice.…”

Section: (Oh) T (Oh)2 T (Oh)3 T (Oh)4 T (Oh)5 (Ohmentioning

confidence: 99%

“…Based on the findings of Perwaiz et al (27), Zhang et al (42), and Zollner (43), the tetrahydroxy bile acids are likely to be formed by hydroxylation at C-12 and C-6 of UDCA (and its conjugates) to form 12␣-hydroxy-␤-muricholic acid (3␣,6␤,7␤,12␣) and 12␣-hydroxy--muricholic acid (3␣,6␣,7␤,12␣). While this work was in progress, Zhang et al (42), reported the presence of 2␤-hydroxy-cholic acid in abcb11 Ϫ/Ϫ mice. We have no information on the sites of hydroxylation of the pentahydroxy metabolites, but one possibility would be 2␤,12␣-dihydroxy-␤-muricholic acid.…”

Section: (Oh) T (Oh)2 T (Oh)3 T (Oh)4 T (Oh)5 (Ohmentioning

confidence: 99%

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Defective canalicular transport and toxicity of dietary ursodeoxycholic acid in theabcb11^−/−mouse: transport and gene expression studies

Liu

Sheps

Forrest

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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The bile salt export pump (BSEP), encoded by the abcb11 gene, is the major canalicular transporter of bile acids from the hepatocyte. BSEP malfunction in humans causes bile acid retention and progressive liver injury, ultimately leading to end-stage liver failure. The natural, hydrophilic, bile acid ursodeoxycholic acid (UDCA) is efficacious in the treatment of cholestatic conditions, such as primary biliary cirrhosis and cholestasis of pregnancy. The beneficial effects of UDCA include promoting bile flow, reducing hepatic inflammation, preventing apoptosis, and maintaining mitochondrial integrity in hepatocytes. However, the role of BSEP in mediating UDCA efficacy is not known. Here, we used abcb11 knockout mice ( abcb11 −/−) to test the effects of acute and chronic UDCA administration on biliary secretion, bile acid composition, liver histology, and liver gene expression. Acutely infused UDCA, or its taurine conjugate (TUDC), was taken up by the liver but retained, with negligible biliary output, in abcb11−/− mice. Feeding UDCA to abcb11−/− mice led to weight loss, retention of bile acids, elevated liver enzymes, and histological damage to the liver. Semiquantitative RT-PCR showed that genes encoding Mdr1a and Mdr1b (canalicular) as well as Mrp4 (basolateral) transporters were upregulated in abcb11−/− mice. We concluded that infusion of UDCA and TUDC failed to induce bile flow in abcb11−/− mice. UDCA fed to abcb11−/− mice caused liver damage and the appearance of biliary tetra- and penta-hydroxy bile acids. Supplementation with UDCA in the absence of Bsep caused adverse effects in abcb11−/− mice.

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Abcb11 Deficiency Induces Cholestasis Coupled to Impaired β-Fatty Acid Oxidation in Mice

Cited by 75 publications

References 55 publications

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

Metabolomics Reveals That Tumor Xenografts Induce Liver Dysfunction

Defective canalicular transport and toxicity of dietary ursodeoxycholic acid in theabcb11^−/−mouse: transport and gene expression studies

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Abcb11 Deficiency Induces Cholestasis Coupled to Impaired β-Fatty Acid Oxidation in Mice

Cited by 75 publications

References 55 publications

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

Metabolomics Reveals That Tumor Xenografts Induce Liver Dysfunction

Defective canalicular transport and toxicity of dietary ursodeoxycholic acid in theabcb11−/−mouse: transport and gene expression studies

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Defective canalicular transport and toxicity of dietary ursodeoxycholic acid in theabcb11^−/−mouse: transport and gene expression studies