title: Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease.
abstract: Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the 'classical' (neutral) and 'alternative' (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH.
authors: University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721, USA.
authors: April D
authors: AD
authors: Lake
authors: Petr
authors: P
authors: Novak
authors: Petia
authors: P
authors: Shipkova
authors: Nelly
authors: N
authors: Aranibar
authors: Donald
authors: D
authors: Robertson
authors: Michael D
authors: MD
authors: Reily
authors: Zhenqiang
authors: Z
authors: Lu
authors: Lois D
authors: LD
authors: Lehman-McKeeman
authors: Nathan J
authors: NJ
authors: Cherrington
mesh_terms: D001647:Bile Acids and Salts / Q000032:analysis / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D016000:Cluster Analysis; D018450:Disease Progression; D005234:Fatty Liver / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D008099:Liver / Q000187:drug effects*; D055432:Metabolomics; D065626:Non-alcoholic Fatty Liver Disease
chemical_list: D001647:Bile Acids and Salts
references: Liver Int. 2012 Jan;32(1):58-69
references: 22098667
references: News Physiol Sci. 1999 Feb;14:24-29
references: 11390813
references: Hepatology. 2005 Jun;41(6):1313-21
references: 15915461
references: Drug Metab Dispos. 2009 May;37(5):1035-45
references: 19196849
references: PLoS One. 2010 Nov 05;5(11):e13858
references: 21079772
references: World J Gastroenterol. 2009 Apr 14;15(14):1677-89
references: 19360911
references: Clin Chim Acta. 2011 Nov 20;412(23-24):2037-45
references: 21855537
references: Ann Med. 2009;41(4):265-78
references: 19353360
references: Toxicol Lett. 1992 Jul;61(2-3):291-304
references: 1641875
references: J Hepatol. 2011 May;54(5):1011-9
references: 21145828
references: Annu Rev Biochem. 2003;72:137-74
references: 12543708
references: Drug Metab Dispos. 2010 Dec;38(12):2293-301
references: 20805291
references: Toxicol Sci. 2008 Mar;102(1):196-204
references: 18032408
references: Clin Chim Acta. 2007 Jul;382(1-2):82-8
references: 17482152
references: QJM. 2010 Feb;103(2):71-83
references: 19914930
references: PLoS One. 2011;6(7):e22094
references: 21760958
references: Am J Physiol Regul Integr Comp Physiol. 2011 Dec;301(6):R1710-22
references: 21957160
references: J Lipids. 2012;2012:754067
references: 21991404
references: Gen Pharmacol. 1995 May;26(3):453-62
references: 7789717
references: Lipids. 2009 Jun;44(6):527-35
references: 19373503
references: Bioorg Med Chem. 2010 Sep 15;18(18):6886-95
references: 20713311
references: Dig Liver Dis. 2012 Apr;44(4):303-10
references: 22169272
references: Dig Dis Sci. 2006 Dec;51(12):2225-34
references: 17080243
references: BMC Bioinformatics. 2009 May 27;10:161
references: 19473525
references: Metabolism. 2011 Mar;60(3):404-13
references: 20423748
references: Mol Pharmacol. 2007 Nov;72(5):1380-90
references: 17724089
references: Nat Rev Drug Discov. 2008 Aug;7(8):678-93
references: 18670431
references: Am J Physiol Gastrointest Liver Physiol. 2009 Sep;297(3):G419-33
references: 19497955
references: Am J Pathol. 2011 Jan;178(1):175-86
references: 21224055
references: Drug Metab Dispos. 2011 Oct;39(10):1954-60
references: 21737566
references: Toxicol Sci. 2011 Oct;123(2):359-67
references: 21747115
references: Gastroenterology. 2005 Apr;128(4):1042-55
references: 15825085
references: J Gastroenterol Hepatol. 2006 Dec;21(12):1807-13
references: 17074018
references: J Clin Gastroenterol. 2006 Mar;40 Suppl 1:S17-29
references: 16540762
references: Wien Med Wochenschr. 2008;158(19-20):542-8
references: 18998069
references: Dig Dis. 2010;28(1):220-4
references: 20460915
references: Drug Metab Dispos. 2009 Oct;37(10):2087-94
references: 19651758
references: Hepatology. 2011 Jul;54(1):344-53
references: 21520200
references: Expert Opin Drug Metab Toxicol. 2011 Apr;7(4):387-98
references: 21320036
references: J Proteome Res. 2011 Jun 3;10(6):2797-806
references: 21563774
references: Toxicol Sci. 2012 Dec;130(2):257-68
references: 22903823
references: Liver Int. 2007 Sep;27(7):920-9
references: 17696930
references: Hepatology. 2012 Sep;56(3):1034-43
references: 22467244
references: Am J Physiol Gastrointest Liver Physiol. 2011 Nov;301(5):G773-82
references: 21778463