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.
Highlights
Transforming growth factor- (TGF) is activated as a result of liver injury, such as cholestasis
Bile acids (BA) homeostasis is Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; BA, bile acid; CA, cholic acid; CHK, choline kinase; CHPT1, choline phosphotransferase 1; CYP; cytochrome P450; FXR, farnesoid X receptor; Lithocholic acid (LCA), lithocholic acid; LPC, lysophosphatidylcholine; LPCAT, lysophosphatidylcholine acyltransferase; OST, organic solute transporter; PCYT1, phosphate cytidylyltransferase 1; PLD, phospholipase D; Partial least squares (PLS), partial least squares; PXR, pregnane X receptor; SLC, solute carrier; SLCO, solute carrier organic anion transporter; SMAD3, MAD homolog 3; SULT, sulfotransferase; T3KL, touro-5cholanic acid-3-one; TC, taurocholate; TCDC, taurochenodeoxycholate; TGF, transforming growth factor-1; THDC, taurohyodeoxycholate; TLC, taurolithocholate; TMDC, tauromurideoxycholate; TNF␣, tumor necrosis factor ␣; TUDC, tauroursodeoxycholate; UPLC-ESI-QTOFMS, ultra-performance liquid chromatography coupled with electrospray ionization quadruple time-of-flight mass spectrometry
Hepatic TGFB1, TGFBR1, and TGFBR2 mRNA levels increased after LCA exposure, TGFBR3 mRNA level did not changed in the livers (Fig. 1)
Summary
Transforming growth factor- (TGF) is activated as a result of liver injury, such as cholestasis. Considering that Smad3-null mice showed attenuated serum ALP activity, a diagnostic indicator of cholangiocyte injury, these results strongly support the view that TGF-SMAD3 signaling mediates an alteration in phospholipid and bile acid metabolism following hepatic inflammation with the biliary injury.—Matsubara, T., N. BA homeostasis is Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; BA, bile acid; CA, cholic acid; CHK, choline kinase; CHPT1, choline phosphotransferase 1; CYP; cytochrome P450; FXR, farnesoid X receptor; LCA, lithocholic acid; LPC, lysophosphatidylcholine; LPCAT, lysophosphatidylcholine acyltransferase; OST, organic solute transporter; PCYT1, phosphate cytidylyltransferase 1; PLD, phospholipase D; PLS, partial least squares; PXR, pregnane X receptor; SLC, solute carrier; SLCO, solute carrier organic anion transporter; SMAD3, MAD homolog 3; SULT, sulfotransferase; T3KL, touro-5cholanic acid-3-one; TC, taurocholate; TCDC, taurochenodeoxycholate; TGF, transforming growth factor-1; THDC, taurohyodeoxycholate; TLC, taurolithocholate; TMDC, tauromurideoxycholate; TNF␣, tumor necrosis factor ␣; TUDC, tauroursodeoxycholate; UPLC-ESI-QTOFMS, ultra-performance liquid chromatography coupled with electrospray ionization quadruple time-of-flight mass spectrometry. This article is available online at http://www.jlr.org maintained by enterohepatic circulation in which greater than 90% are reabsorbed from the small intestine and transported to the liver
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