title: 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.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Matsubara
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Misako
authors.initials: M
authors.lastname: Sato
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kang
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Flanders
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ikeda
authors.forename: Hans
authors.initials: H
authors.lastname: Luecke
authors.forename: Lalage M
authors.initials: LM
authors.lastname: Wakefield
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002478:Cells, Cultured; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008095:Lithocholic Acid; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010743:Phospholipids / Q000378:metabolism*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D010743:Phospholipids; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D008095:Lithocholic Acid