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Lithocholic acid disrupts phospholipid and sphingolipid homeostasis leading to cholestasis in mice.

ABSTRACT: UNLABELLED:Lithocholic acid (LCA) is an endogenous compound associated with hepatic toxicity during cholestasis. LCA exposure in mice resulted in decreased serum lysophosphatidylcholine (LPC) and sphingomyelin levels due to elevated lysophosphatidylcholine acyltransferase (LPCAT) and sphingomyelin phosphodiesterase (SMPD) expression. Global metabolome analysis indicated significant decreases in serum palmitoyl-, stearoyl-, oleoyl-, and linoleoyl-LPC levels after LCA exposure. LCA treatment also resulted in decreased serum sphingomyelin levels and increased hepatic ceramide levels, and induction of LPCAT and SMPD messenger RNAs (mRNAs). Transforming growth factor-? (TGF-?) induced Lpcat2/4 and Smpd3 gene expression in primary hepatocytes and the induction was diminished by pretreatment with the SMAD3 inhibitor SIS3. Furthermore, alteration of the LPCs and Lpcat1/2/4 and Smpd3 expression was attenuated in LCA-treated farnesoid X receptor-null mice that are resistant to LCA-induced intrahepatic cholestasis. CONCLUSION:This study revealed that LCA induced disruption of phospholipid/sphingolipid homeostasis through TGF-? signaling and that serum LPC is a biomarker for biliary injury.

SUBMITTER: Matsubara T

PROVIDER: S-EPMC3077083 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Lithocholic acid disrupts phospholipid and sphingolipid homeostasis leading to cholestasis in mice.

Matsubara Tsutomu T Tanaka Naoki N Patterson Andrew D AD Cho Joo-Youn JY Krausz Kristopher W KW Gonzalez Frank J FJ

Hepatology (Baltimore, Md.) 20110401 4

<h4>Unlabelled</h4>Lithocholic acid (LCA) is an endogenous compound associated with hepatic toxicity during cholestasis. LCA exposure in mice resulted in decreased serum lysophosphatidylcholine (LPC) and sphingomyelin levels due to elevated lysophosphatidylcholine acyltransferase (LPCAT) and sphingomyelin phosphodiesterase (SMPD) expression. Global metabolome analysis indicated significant decreases in serum palmitoyl-, stearoyl-, oleoyl-, and linoleoyl-LPC levels after LCA exposure. LCA treatme ...[more]

PMID: 21480330

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Project description:UNLABELLED:Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease that can develop into cirrhosis, hepatic failure, and hepatocellular carcinoma. Although several metabolic pathways are disrupted and endogenous metabolites may change in NASH, the alterations in serum metabolites during NASH development remain unclear. To gain insight into the disease mechanism, serum metabolite changes were assessed using metabolomics with ultraperformance 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-?-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 subfamily C member [Abcc] 1/4/5 and organic solute transporter ?), and 12-HETE synthesis (arachidonate 12-lipoxygenase) were significantly up-regulated. In contrast, the expression of solute carrier family 10 member 1 (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 the MCD diet with methionine 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-? and transforming growth factor-?1 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 proinflammatory cytokines. Finally, induction of hepatitis in ob/ob mice by D-galactosamine injection led to similar changes in serum metabolites and related gene expression. CONCLUSION:Phospholipid and bile acid metabolism is disrupted in NASH, likely due to enhanced hepatic inflammatory signaling.

Dataset Information

Lithocholic acid disrupts phospholipid and sphingolipid homeostasis leading to cholestasis in mice.

Publications

Lithocholic acid disrupts phospholipid and sphingolipid homeostasis leading to cholestasis in mice.

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