TGF-β-SMAD3 signaling mediates hepatic bile acid and phospholipid metabolism following lithocholic acid-induced liver injury.

Abstract

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.

• Authors: 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
• Journal: Journal of lipid research (J Lipid Res) Vol. 53 Issue 12 Pg. 2698-707 (Dec 2012) ISSN: 1539-7262 [Electronic] United States
• PMID: 23034213 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bile Acids and Salts
• Phospholipids
• Smad3 Protein
• Smad3 protein, mouse
• Transforming Growth Factor beta
• Lithocholic Acid

Topics

• Animals
• Bile Acids and Salts (metabolism)
• Cells, Cultured
• Hep G2 Cells
• Hepatocytes (chemistry, drug effects, metabolism)
• Humans
• Lithocholic Acid
• Liver (drug effects, injuries, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Phospholipids (metabolism)
• Signal Transduction
• Smad3 Protein (metabolism)
• Transforming Growth Factor beta (metabolism)