The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases - PubMed (original) (raw)

Review

. 2016 Sep;57(9):1636-43.

doi: 10.1194/jlr.R069286. Epub 2016 Jul 26.

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Review

The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases

Masayuki Nagahashi et al. J Lipid Res. 2016 Sep.

Abstract

Based on research carried out over the last decade, it has become increasingly evident that bile acids act not only as detergents, but also as important signaling molecules that exert various biological effects via activation of specific nuclear receptors and cell signaling pathways. Bile acids also regulate the expression of numerous genes encoding enzymes and proteins involved in the synthesis and metabolism of bile acids, glucose, fatty acids, and lipoproteins, as well as energy metabolism. Receptors activated by bile acids include, farnesoid X receptor α, pregnane X receptor, vitamin D receptor, and G protein-coupled receptors, TGR5, muscarinic receptor 2, and sphingosine-1-phosphate receptor (S1PR)2. The ligand of S1PR2, sphingosine-1-phosphate (S1P), is a bioactive lipid mediator that regulates various physiological and pathophysiological cellular processes. We have recently reported that conjugated bile acids, via S1PR2, activate and upregulate nuclear sphingosine kinase 2, increase nuclear S1P, and induce genes encoding enzymes and transporters involved in lipid and sterol metabolism in the liver. Here, we discuss the role of bile acids and S1P signaling in the regulation of hepatic lipid metabolism and in hepatobiliary diseases.

Keywords: bile duct cancer; fatty acid; liver metabolism; lysosphingolipid; sphingosine kinase.

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Figures

Fig. 1.

Fig. 1.

Metabolism of cholesterol and bile acid synthesis. The primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), are formed from cholesterol in the liver and stored in the gallbladder. The secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), are formed by microbiota. Primary conjugated bile acids stimulate S1PR2 in the liver. On the other hand, secondary conjugated bile acids stimulate S1PR2 in the intestine. *These bile acids were shown to stimulate S1PR2 previously (8). GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; TCDCA, taurochenodeoxycholic acid; GDCA, glycodeoxycholic acid; TDCA, taurodeoxycholic acid; GLCA, glycolithocholic acid; TLCA, taurolithocholic acid; GUDCA, glycoursodeoxycholic acid, TUDCA, tauroursodeoxycholic acid.

Fig. 2.

Fig. 2.

Model of regulation of hepatic genes encoding enzymes involved in nutrient metabolism by conjugated bile acids and S1P. Conjugated bile acids and S1P activate S1PR2 and then activate nuclear SphK2 via cell signaling pathways such as AKT or ERK1/2 (8, 11, 54), increasing the levels of S1P in the nucleus. Nuclear S1P inhibits specific HDACs, causing an increase in acetylation of histones and upregulation of genes encoding nuclear receptors and enzymes involved in lipid and glucose metabolism. CBA, conjugated bile acid; Sph, sphingosine.

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