Sphingosine‐1‐phosphate receptor 2: A novel bile acid receptor and regulator of hepatic lipid metabolism?
Authors: John Y.L. Chiang
Journal: Hepatology (2014)

Potential conflict of interest: Nothing to report. See Article on Page 1216 Dysregulation of hepatic lipid metabolism is a major contributing factor for the development of hepatic steatosis and the pathogenesis of nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids have lipid‐lowering effects, but the underlying mechanisms are very complex and not fully understood (review in Fuchs et al.1). It has been known for a long time that bile acid pool size is inversely correlated to serum triglyceride levels in human patients. Bile acid sequestrants reduce bile acid pool size but increase serum triglycerides. Conversely, bile acid treatment in hypertriglyceridemia and gallstone patients decreased serum triglycerides and very low‐density lipoprotein production. The discovery of farnesoid X receptor (FXR) as a bile acid–activated receptor has generated a plethora of research into the roles of bile acids in the regulation of hepatic lipid metabolism in recent years (review in Li and Chiang2). Farnesoid X receptor is activated by the primary bile acids chenodeoxycholic acid and cholic acid to inhibit bile acid synthesis by a feedback mechanism (Fig. 1). In the liver, FXR induces the small heterodimer partner (SHP), which inhibits cholesterol 7α‐hydroxylase (CYP7A1) gene transcription and bile acid synthesis. In the intestine, FXR induces fibroblast growth factor 15 (FGF15 or human orthologue FGF19), which is secreted into the blood circulation to hepatocytes to activate FGF receptor 4 (FGFR4) that activates the mitogen activated protein kinase (MAPK)/extracellular receptor kinase 1/2 (ERK1/2) pathway to inhibit CYP7A1. Cholic acid and synthetic FXR agonists have been shown to reduce serum triglycerides in diabetic and obese mice. Consistently, FXR–/– mice have increased serum triglycerides and proatherogenic lipoprotein profiles.Figure 1: Complex mechanisms of bile acid signaling in the regulation of lipid metabolism in hepatocytes. Bile acids are the end products of cholesterol catabolism. In the bile acid synthetic pathway CYP7A1 is the first and rate‐limiting enzyme. The primary bile acids cholic acid and chenodeoxycholic acid are endogenous ligands of FXR. In the liver, FXR induces SHP, which inhibits Cyp7A1 gene transcription. In the intestine, FXR induces FGF15, which is secreted to the blood circulation to activate the hepatic fibroblast growth factor receptor 4 to activate mainly the MAPK/ERK1/2 pathway to inhibit CYP7A1 and sterol 12α‐hydroxylase (CYP8B1) gene transcription. It is known that FXR stimulates energy metabolism by inducing ApoCII and inhibiting ApoCIII to activate lipoprotein lipase, which hydrolyzes triglycerides carried by very low‐density lipoproteins and chylomicrons in peripheral tissues. Also, FXR induces peroxisome proliferator–activated receptor α to stimulate fatty acid oxidation and clearance; FXR regulates lipoprotein metabolism by inducing the very low‐density lipoprotein receptor and phospholipid transfer protein and inhibiting ApoB1 and microsomal triglyceride transport protein to inhibit very low‐density lipoprotein secretion. It also has an anti‐inflammatory function by inhibiting NFκB‐mediated inflammatory cytokine production in hepatocytes and enterocytes. The FXR‐independent pathways also are involved in the regulation of bile acid synthesis and liver metabolism. A secondary bile acid–activated G protein–coupled receptor, TGR5, is expressed in hepatic endothelial cells and Kupffer cells but not hepatocytes. It may regulate lipid metabolism by indirect mechanisms. In brown adipose tissues, TGR5/cAMP signaling may stimulate energy metabolism by inducing a type 2 deiodinase, which activates thyroxine to triiodothyronine. In the intestine, TGR5 signaling protects barrier function and inflammation and may indirectly protect hepatocytes against inflammation. The conjugated bile acid TCA selectively activates S1PR2 in hepatocytes. Extracellular signal activates SphK1, which is translocated to the plasma membrane to phosphorylate sphingosine to S1P, which activates membrane S1PRs by a paracrine/autocrine mechanism. Growth factors (epidermal growth factor, FGFR4, etc.) and phorbol esters activate protein kinase C, which activates ERK1/2 of the MAPK pathway to phosphorylate SphK2, which is then is translocated to the nucleus to bind to HDAC1/2. Sphingosine‐1‐phosphate signaling activates ERK1/2 and AKT in insulin receptor signaling pathway. Nuclear SphK2–generated S1P has been shown to bind to chromatin and to inhibit HDAC1/2. Inhibition of HDAC1/2 results in activation of histone acetylases, which stimulates expression of SREBP‐1c, which induces all genes in lipogenesis (fatty acid synthase, acetyl‐coenzyme A carboxylase, etc.), and CYP7A1 in bile acid synthesis. On the other hand, the FXR/SHP pathway inhibits SREBP‐1c and CYP7A1 gene transcription by recruiting HDAC1/2, histone methyltransferase G9a, and histone lysine‐specific demethylase‐1 to inhibit lipogenesis and bile acid synthesis. These positive and negative regulations modulate hepatic lipid homeostasis. Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; FGFR4, fibroblast growth factor receptor 4; IR, insulin receptor; LSD‐1, lysine‐specific demethylase‐1; MTTP, microsomal triglyceride transport protein; NF‐κB, nuclear factor κB; PKC, protein kinase C; PLTP, phospholipid transfer protein; PPARα, peroxisome proliferator–activated receptor α; VLDLR, very low‐density lipoprotein receptor.Farnesoid X receptor signaling may regulate hepatic lipid metabolism by several mechanisms. It has been reported that activation of FXR by bile acids or FXR agonists inhibits steroid response element binding protein‐1c (SREBP‐1c)‐mediated hepatic lipogenesis. It was suggested that the FXR/SHP pathway might inhibit expression of the genes in lipogenesis and very low‐density lipoprotein metabolism (Fig. 1). The FXR agonists stimulate triglyceride clearance. Transgenic overexpression of FGF19 has been shown to increase metabolic rate in mice, but the mechanism is not clear. More importantly, recent studies showed that bile acids and FXR agonists had an anti‐inflammatory function through the inhibition of nuclear factor‐κB (NFκB)–mediated inflammatory cytokine production in hepatocytes and enterocytes.3 However, how FXR signaling inhibits NF‐κB activity is not clear. Expression of SREBP‐1c and its target genes is not reduced in FXR–/– mice, suggesting that FXR‐independent mechanisms may also be involved in the triglyceride‐lowering effect of bile acids. Secondary bile acids (lithocholic acid and deoxycholic acid) and their taurine conjugates are activators of the G protein bile acid receptor 1 (TGR5, aka Gpbar1). In the digestive tract, TGR5 is expressed in the gallbladder epithelium and in the intestine. In the liver, TGR5 is expressed in Kupffer cells and sinusoidal endothelial cells, as well as in cholangiocytes but not in hepatocytes. Activation of TGR5 signaling stimulates energy metabolism in brown adipose tissue, protects the intestinal barrier function, and alleviates inflammation in animal models of inflammatory bowel diseases. However, TGR5–/– mice have no obvious liver metabolic phenotype. Activation of TGR5 has been shown to protect the liver from inflammation, but the underlying mechanism is not clear. Agonists of TGR5 increase insulin secretion from β‐cells and glycogen‐like peptide‐1 secretion from enteroendocrine cells and may contribute to the amelioration of liver inflammation and insulin resistance. Another G protein–coupled receptor, sphingosine‐1‐phosphate receptor 2 (S1PR2), has recently been reported as a conjugated bile acid–activated receptor.5 Taurocholic acid (TCA) is the most abundant bile acid in humans and mice and an efficacious activator of S1PR2 in hepatocytes. Sphingosine‐1‐phosphate (S1P) activates an S1P family of Gαi‐coupled receptors (S1PR1‐5). The S1P kinases (SphK1 and SphK2) phosphorylate sphingosine to S1P: SphK1 is located in the cytosol, whereas SphK2 is localized in the nucleus. In hepatocytes, S1PR2 signaling activates ERK1/2 in the MAPK signaling pathways and AKT in insulin signaling (Fig. 1). Sphingolipid metabolites have diverse functions in endothelial cells, including immune response, lymphatic trafficking, and vascular integrity.6 In endothelial cells, S1P/S1PR–mediated signaling activates NF‐κB in proinflammatory responses. The role of S1PR2/SphK2/S1P on hepatic lipid metabolism has not been studied. In this issue of Hepatology, Nagahashi et al.7 report a novel finding that the S1PR2/SphK2/S1P signaling pathway might play a key role in the control of hepatic lipid metabolism in mice. A previous in vitro study reported that the nuclear SphK2‐generated S1P bound to and inhibited the activity of histone deacetylases 1 and 2 (HDAC1/2) and increased histone acetylation and expression of cyclin‐dependent kinase inhibitor p21 and cFos of MCF‐7 and HeLa cells.8 The current in vivo study showed that in S1PR2–/– and SphK2–/– mice acetylated histone 3 and histone 4 levels were reduced and these reductions correlated to reduced mRNA expression levels of SREBP‐1c and its regulated genes in lipid metabolism and bile acid synthesis (not CYP7A1). Furthermore, overexpression of S1PR2 induced these hepatic genes (including CYP7A1) in wild‐type and S1PR2–/– mice, but not in SphK2–/– mice, suggesting that SphK2 is necessary for mediating S1PR2 signaling in lipid metabolism. A high‐fat/high‐cholesterol diet and a lithogenic diet (containing high cholesterol and cholic acid) induced SphK2, but not SphK1, expression in wild‐type mouse liver. It is important to note that SphK2–/– mice on a chow diet had markedly elevated serum triglycerides and aspartate transaminase and alanine transaminase levels compared to wild‐type mice. High‐fat diet feeding increased serum triglycerides and aspartate transaminase and alanine transaminase levels in wild‐type mice as expected but did not further increase serum triglyceride and aspartate transaminase and alanine transaminase levels in SphK2–/– mice. These data imply that TCA/S1PR2/SphK2/S1P signaling may play a key role in mediating the anti‐inflammatory function of bile acids in hepatocytes. It is important to study whether or not the TCA/S1PR2/SphK2/S1P signaling pathway modulates NF‐κB‐mediated proinflammatory cytokine production via epigenetic mechanisms in hepatocytes. Paradoxically, both SHP and CYP7A1 mRNA expression levels were significantly increased in wild‐type and S1PR2–/– mice by overexpressing S1PR2. It has been reported that SHP recruits HDAC1/2, histone lysine‐specific demethylase‐1, histone methyltransferase G9a,and other chromatin modifying enzymes to inhibit CYP7A1 gene transcription.9 Thus, TCA may activate the SHP/HDAC/lysine‐specific demethylase‐1/G9a pathway to inhibit and activate the S1PR2/SphK2/S1P/HDAC1/2 pathway to induce CYP7A1 expression levels to modulate bile acid homeostasis. Histone acetylation and methylation of the chromatin in gene promoters has emerged as a key mechanism for the regulation of liver metabolism. This study uncovered a novel role of the TCA/S1PR2/SphK2/S1P pathway in the control of hepatic lipid metabolism. Further detailed study is needed to (1) identify the liver metabolic phenotypes and differentially regulated genes and pathways in S1PR2–/– and SphK2–/– mice, (2) confirm the role of the S1PR2/SphK2/S1P pathway in the control of hepatic lipid gene expression by epigenetic mechanisms, and (3) identify other metabolic pathways and mechanisms that may be involved in the pleiotropic effects of S1P and its implication in the pathogenesis of nonalcoholic fatty liver disease. Inhibitors targeted to HDAC and histone methyltransferase activity are currently being developed as drug therapies for the treatment of cancer and other human diseases and may have potential for treating inflammatory liver–related metabolic diseases, such as nonalcoholic fatty liver disease and diabetes.