Year: 2015
Type: letter
Abstract: Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. We thank Carulli et al. for their great interest in our recent study and insightful comments on bile acid–mediated regulation of lipid metabolism.1 Our study clearly shows that sphingosine‐1 phosphate receptor 2 (S1PR2), which is activated by conjugated bile acids, regulates nuclear sphingosine kinase 2, allowing for the up‐regulation of genes involved in lipid and sterol metabolism by an epigenetic mechanism.1 Conjugated bile acid–mediated activation of S1PR2 may allow for up‐regulation of lipid secretion through very low‐density lipoprotein and increase oxidation of fatty acids (Fig. 1). Intriguingly, S1PR2 also activates the extracellular signal–regulated kinase and AKT signaling pathways, probably through epidermal growth factor receptor.2 Activation of pyruvate dehydrogenase kinase and protein kinase Cζ, a branch of the AKT pathway, is necessary for maximum induction of small heterodimer partner (SHP).3 Watanabe et al. reported that SHP represses sterol regulatory element binding protein 1c, down‐regulating fatty acid and triglyceride synthesis.4 Our study indicated that S1PR2 may function to both increase output of lipids from the liver and decrease lipid synthesis through farnesoid X receptor–SHP induction. Also, S1PR2 appears to help coordinately regulate glucose metabolism as bile acids have been shown to be as potent as insulin in activating AKT and glycogen synthase and down‐regulating gluconeogenesis genes.5 In a feed/fast cycle, conjugated bile acids returning from the intestines probably rapidly activate sphingosine kinase 2, which is required for the induction of genes involved in lipid metabolism and secretion through an epigenetic mechanism. Activation of AKT:pyruvate dehydrogenase kinase:protein kinase Cζ increases the phosphorylation of farnesoid X receptor and allows maximal induction of SHP, a nuclear receptor involved in repressing genes by associating with other nuclear receptors (hepatocyte nuclear factor 4α, liver X receptor, others) and possibly chromatin modifying cofactors. Hence, S1PR2 may play a role in both the induction and the repression of hepatic gene expression, depending upon the time in the feed/fast cycle. Inflammation, which inhibits the insulin signaling pathway (AKT), may disrupt these tightly regulated metabolic regulatory mechanisms, allowing for lipid accumulation and increased risk for nonalcoholic fatty liver disease.Figure 1: Role of sphingosine 1‐phosphate receptor 2 in the regulation of hepatic metabolism. Abbreviations: CBA, conjugated bile acid; ERK, extracellular signal–regulated kinase; FXR, farnesoid X receptor; PDK, pyruvate dehyrdrogenase kinase; PKC, protein kinase C; SHP, small heterodimer partner; SphK2, sphingosine kinase 2; S1PR2, sphingosine‐1 phosphate receptor 2; VLDL, very low‐density lipoprotein.
Source: Hepatology
DOI: 10.1002/hep.27961
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2120177507