| Disruption of phospholipid and bile acid homeostasis in mice with nonalcoholic steatohepatitis. | |
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MedLine Citation:
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PMID: 22290395 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease. , can develop into cirrhosis, hepatic failure, and hepatocellular carcinoma. While several metabolic pathways are disrupted, the mechanism of NASH development remains unclear. While several metabolic pathways are disrupted and endogenous metabolites may change in NASH, alterations in serum metabolites during NASH development remain unclear. To gain insight into disease mechanism, Serum metabolite changes were assessed using metabolomics with ultra-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry and a conventional mouse NASH model induced by a methionine- and choline-deficient (MCD) diet. Significant decreases in serum palmitoyl-, stearoyl-, and oleoyl-lysophosphatidylcholine (LPC) and marked increases in tauro-β-muricholate, taurocholate, and 12-hydroxyeicosatetraenoic acid (12-HETE) were detected in mice with NASH. In agreement with these metabolite changes, hepatic mRNAs encoding enzymes and proteins involved in LPC degradation [lysophosphatidylcholine acyltransferase (Lpcat) 1-4], basolateral bile acid excretion [ATP-binding cassette sub-family C member (Abcc) 1/4/5 and organic solute transporter β], and 12-HETE synthesis (arachidonate 12-lipoxygenase) were significantly up-regulated. In contrast, the expression of sodium/taurocholate transport protein (Slc10a1) and solute carrier organic anion transporter family member (Slco) 1a1 and 1b2, responsible for transporting bile acids into hepatocytes, were markedly suppressed. Supplementation of methionine to the MCD diet revealed that the changes in serum metabolites and the related gene expression were derived from steatohepatitis, but not dietary choline deficiency or steatosis. Furthermore, Tumor necrosis factor-α and transforming growth factor-β1 induced the expression of Lpcat2/4 and Abcc1/4 and down-regulated Slc10a1 and Slco1a1 in primary hepatocytes, suggesting an association between the changes in serum LPC and bile acids and pro-inflammatory cytokines. Finally, induction of hepatitis to ob/ob mice by D-galactosamine injection led to similar changes in serum metabolites and the related gene expression. Conclusion: Phospholipid and bile acid metabolism is disrupted in NASH, likely due to enhanced hepatic inflammatory signaling. Serum LPC and bile acids may be biomarkers of NASH. (HEPATOLOGY 2012.). |
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Authors:
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Naoki Tanaka; Tsutomu Matsubara; Kristopher W Krausz; Andrew D Patterson; Frank J Gonzalez |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-30 |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: - ISSN: 1527-3350 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-31 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 American Association for the Study of Liver Diseases. |
Affiliation:
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Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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