Document Detail

TGF-β-SMAD3 signaling mediates hepatic bile acid and phospholipid metabolism following lithocholic acid-induced liver injury.
MedLine Citation:
PMID:  23034213     Owner:  NLM     Status:  MEDLINE    
Transforming growth factor-β (TGFβ) is activated as a result of liver injury, such as cholestasis. However, its influence on endogenous metabolism is not known. This study demonstrated that TGFβ regulates hepatic phospholipid and bile acid homeostasis through MAD homolog 3 (SMAD3) activation as revealed by lithocholic acid-induced experimental intrahepatic cholestasis. Lithocholic acid (LCA) induced expression of TGFB1 and the receptors TGFBR1 and TGFBR2 in the liver. In addition, immunohistochemistry revealed higher TGFβ expression around the portal vein after LCA exposure and diminished SMAD3 phosphorylation in hepatocytes from Smad3-null mice. Serum metabolomics indicated increased bile acids and decreased lysophosphatidylcholine (LPC) after LCA exposure. Interestingly, in Smad3-null mice, the metabolic alteration was attenuated. LCA-induced lysophosphatidylcholine acyltransferase 4 (LPCAT4) and organic solute transporter β (OSTβ) expression were markedly decreased in Smad3-null mice, whereas TGFβ induced LPCAT4 and OSTβ expression in primary mouse hepatocytes. In addition, introduction of SMAD3 enhanced the TGFβ-induced LPCAT4 and OSTβ expression in the human hepatocellular carcinoma cell line HepG2. In conclusion, considering that Smad3-null mice showed attenuated serum ALP activity, a diagnostic indicator of cholangiocyte injury, these results strongly support the view that TGFβ-SMAD3 signaling mediates an alteration in phospholipid and bile acid metabolism following hepatic inflammation with the biliary injury.
Tsutomu Matsubara; Naoki Tanaka; Misako Sato; Dong Wook Kang; Kristopher W Krausz; Kathleen C Flanders; Kazuo Ikeda; Hans Luecke; Lalage M Wakefield; Frank J Gonzalez
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2012-10-03
Journal Detail:
Title:  Journal of lipid research     Volume:  53     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-09     Completed Date:  2013-04-25     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2698-707     Citation Subset:  IM    
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MeSH Terms
Bile Acids and Salts / metabolism*
Cells, Cultured
Hep G2 Cells
Hepatocytes / chemistry,  drug effects,  metabolism
Lithocholic Acid
Liver / drug effects,  injuries,  metabolism*
Mice, Inbred C57BL
Mice, Nude
Phospholipids / metabolism*
Signal Transduction*
Smad3 Protein / metabolism*
Transforming Growth Factor beta / metabolism*
Reg. No./Substance:
0/Bile Acids and Salts; 0/Phospholipids; 0/Smad3 Protein; 0/Smad3 protein, mouse; 0/Transforming Growth Factor beta; 5QU0I8393U/Lithocholic Acid

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