Teng Liu1,2,3,4,5, Ren-Xue Wang2, Jun Han3, Chen-Zhi Hao4,5, Yi-Ling Qiu4,5, Yan-Yan Yan1, Li-Ting Li4,5, Neng-Li Wang1, Jing-Yu Gong1, Yi Lu4,5, Mei-Hong Zhang1, Xin-Bao Xie4,5, Jun-Cong Yang3, Yi-Jie You1, Jia-Qi Li1, A S Knisely6, Christoph H Borchers3,7,8,9, Victor Ling2, Jian-She Wang4,5. 1. Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China. 2. BC Cancer Agency, Vancouver, BC, Canada. 3. University of Victoria-Genome BC Proteomics Centre, University of Victoria, Victoria, BC, Canada. 4. Department of Pediatrics, Shanghai Medical College, Fudan University, Shanghai, China. 5. The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China. 6. Institut für Pathologie, Medizinische Universität Graz, Graz, Österreich/Austria. 7. Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada. 8. Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University, Montreal, QC, Canada. 9. Proteomics Centre, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada.
Abstract
BACKGROUND & AIMS: Genetic defects causing dysfunction in bile salt export pump (BSEP/ABCB11) lead to liver diseases. ABCB11 mutations alter the bile acid metabolome. We asked whether profiling plasma bile acids could reveal compensatory mechanisms and track genetic and clinical status. METHODS: We compared plasma bile acids in 17 ABCB11-mutated patients, 35 healthy controls and 12 genetically undiagnosed cholestasis patients by ultra-high-performance liquid chromatography/multiple-reaction monitoring-mass spectrometry (UPLC/MRM-MS). We developed an index to rank bile acid hydrophobicity, and thus toxicity, based on LC retention times. We recruited 42 genetically diagnosed hereditary cholestasis patients, of whom 12 were presumed to have impaired BSEP function but carried mutations in genes other than ABCB11, and 8 healthy controls, for further verification. RESULTS: The overall hydrophobicity indices of total bile acids in both the ABCB11-mutated group (11.89 ± 1.07 min) and the undiagnosed cholestasis group (11.46 ± 1.07 min) were lower than those of healthy controls (13.69 ± 0.77 min) (both p < 0.005). This was owing to increased bile acid modifications. Secondary bile acids were detected in patients without BSEP expression, suggesting biliary bile acid secretion through alternative routes. A diagnostic panel comprising lithocholic acid (LCA), tauro-LCA, glyco-LCA and hyocholic acid was identified that could differentiate the ABCB11-mutated cohort from healthy controls and undiagnosed cholestasis patients (AUC=0.946, p < 0.0001) and, in non-ABCB11-mutated cholestasis patients, could distinguish BSEP dysfunction from normal BSEP function (9/12 vs 0/38, p < 0.0000001). CONCLUSIONS: Profiling of plasma bile acids has provided insights into cholestasis alleviation and may be useful for the clinical management of cholestatic diseases.
BACKGROUND & AIMS: Genetic defects causing dysfunction in bile salt export pump (BSEP/ABCB11) lead to liver diseases. ABCB11 mutations alter the bile acid metabolome. We asked whether profiling plasma bile acids could reveal compensatory mechanisms and track genetic and clinical status. METHODS: We compared plasma bile acids in 17 ABCB11-mutated patients, 35 healthy controls and 12 genetically undiagnosed cholestasispatients by ultra-high-performance liquid chromatography/multiple-reaction monitoring-mass spectrometry (UPLC/MRM-MS). We developed an index to rank bile acid hydrophobicity, and thus toxicity, based on LC retention times. We recruited 42 genetically diagnosed hereditary cholestasispatients, of whom 12 were presumed to have impaired BSEP function but carried mutations in genes other than ABCB11, and 8 healthy controls, for further verification. RESULTS: The overall hydrophobicity indices of total bile acids in both the ABCB11-mutated group (11.89 ± 1.07 min) and the undiagnosed cholestasis group (11.46 ± 1.07 min) were lower than those of healthy controls (13.69 ± 0.77 min) (both p < 0.005). This was owing to increased bile acid modifications. Secondary bile acids were detected in patients without BSEP expression, suggesting biliary bile acid secretion through alternative routes. A diagnostic panel comprising lithocholic acid (LCA), tauro-LCA, glyco-LCA and hyocholic acid was identified that could differentiate the ABCB11-mutated cohort from healthy controls and undiagnosed cholestasispatients (AUC=0.946, p < 0.0001) and, in non-ABCB11-mutated cholestasispatients, could distinguish BSEPdysfunction from normal BSEP function (9/12 vs 0/38, p < 0.0000001). CONCLUSIONS: Profiling of plasma bile acids has provided insights into cholestasis alleviation and may be useful for the clinical management of cholestatic diseases.
Authors: Renxue Wang; Jonathan A Sheps; Lin Liu; Jun Han; Patrick S K Chen; Jason Lamontagne; Peter D Wilson; Ian Welch; Christoph H Borchers; Victor Ling Journal: J Lipid Res Date: 2018-11-11 Impact factor: 5.922