Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism

Abstract

The liver is the central organ involved in lipid metabolism. Dyslipidemia and its related disorders, including non-alcoholic fatty liver disease (NAFLD), obesity and other metabolic diseases, are of increasing public health concern due to their increasing prevalence in the population. Besides their well-characterized functions in cholesterol homoeostasis and nutrient absorption, bile acids are also important metabolic regulators and function as signaling hormones by activating specific nuclear receptors, G-protein coupled receptors, and multiple signaling pathways. Recent studies identified a new signaling pathway by which conjugated bile acids (CBA) activate the extracellular regulated protein kinases (ERK1/2) and protein kinase B (AKT) signaling pathway via sphingosine-1-phosphate receptor 2 (S1PR2). CBA-induced activation of S1PR2 is a key regulator of sphingosine kinase 2 (SphK2) and hepatic gene expression. This review focuses on recent findings related to the role of bile acids/S1PR2-mediated signaling pathways in regulating hepatic lipid metabolism.

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

“…In addition, TCA induced a rapid downregulation of the gluconeogenesis genes, PEPCK and G6Pase, and a marked upregulation of SHP mRNA in the livers (42). This illustrates that bile acid activation of S1PR2 has insulin-like activity in hepatic glucose regulation (9). Further, it has been reported that hepatic overexpression of SphK2 in mice led to elevated S1P and reduced ceramide, sphingomyelin, and glucosylceramide in plasma and liver, and ameliorated glucose intolerance and insulin resistance by improving hepatic insulin signaling (44).…”

“…These data suggest that a bile acid induced an increase in SphK2 through S1PR2 activation. In fact, mice deficient in SphK2 also rapidly developed fatty livers on a high-fat diet, suggesting the importance of S1PR2 and SphK2 in regulating liver lipid metabolism (9,11). In mice fed a high-fat diet, overexpression of SphK2 led to elevated S1P and reduced ceramide, sphingomyelin, and glucosylceramide in plasma and in the liver (44).…”

“…2). This illustrates the importance of S1PR2 and SphK2 in regulating genes encoding enzymes and transporters involved in nutrient metabolism BILE ACIDS AND S1PR2 SIGNALING IN REGULATING HEPATIC GLUCOSE METABOLISM Bile acid-mediated activation of the ERK1/2 and AKT signaling pathways through S1PR2 was shown to play an important role in hepatic lipid metabolism and glucose regulation (9,11). In fact, in primary rat hepatocytes, bile acids activated glycogen synthesis to a similar level as insulin due to the effect of AKT and ERK1/2 signaling (10,11).…”

“…Dent and colleagues have previously reported that conjugated bile acids activate protein kinase B (AKT) and extracellular regulated protein kinases 1 and 2 (ERK1/2) via Gi protein-coupled receptors (10). Bile acids have also been implicated in the inflammatory response and various liver diseases, as well as the promotion of cancers of the colon, liver, and bile duct (9). Increasingly, bile acids have been proposed to also function as hormones and nutrient signaling molecules that contribute to glucose and lipid metabolism.…”

“…1). S1PR2 is highly expressed in liver hepatocytes (9). The S1PR2 antagonist, JTE-013, has been shown to inhibit activation of ERK1/2 and AKT by S1P, TCA, taurodeoxycholic acid, tauroursodeoxycholic acid, glycocholic acid, and glycodeoxycholic acid (8) (Fig.…”