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-β (TGF-β) 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-β signaling and that serum LPC is a biomarker for biliary injury.

• Authors: Tsutomu Matsubara, Naoki Tanaka, Andrew D Patterson, Joo-Youn Cho, Kristopher W Krausz, Frank J Gonzalez
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 53 Issue 4 Pg. 1282-93 (Apr 2011) ISSN: 1527-3350 [Electronic] United States
• PMID: 21480330 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: American Association for the Study of Liver Diseases.

Chemical References

• Ceramides
• Lysophosphatidylcholines
• Phospholipids
• RNA, Messenger
• Sphingolipids
• Sphingomyelins
• Transforming Growth Factor beta
• Lithocholic Acid
• 1-Acylglycerophosphocholine O-Acyltransferase
• Smpd3 protein, mouse
• Sphingomyelin Phosphodiesterase

Topics

• 1-Acylglycerophosphocholine O-Acyltransferase (biosynthesis)
• Animals
• Ceramides (biosynthesis)
• Cholestasis
• Female
• Homeostasis (drug effects)
• Lithocholic Acid (blood, toxicity)
• Lysophosphatidylcholines (blood)
• Metabolome
• Mice
• Mice, Inbred C57BL
• Phospholipids (metabolism)
• RNA, Messenger (metabolism)
• Sphingolipids (metabolism)
• Sphingomyelin Phosphodiesterase (biosynthesis)
• Sphingomyelins (blood)
• Transforming Growth Factor beta (physiology)