Sphingosine Kinases/Sphingosine 1-Phosphate Signaling in Hepatic Lipid Metabolism

Abstract

The ever-increasing prevalence of metabolic diseases such as dyslipidemia and diabetes in the western world continues to be of great public health concern. Biologically active sphingolipids, such as sphingosine 1-phosphate (S1P) and ceramide, are important regulators of lipid metabolism. S1P not only directly functions as an active intracellular mediator, but also activates multiple signaling pathways via five transmembrane G-protein coupled receptors (GPCRs), S1PR1-5. S1P is exclusively formed by sphingosine kinases (SphKs). Two isoforms of SphKs, SphK1 and SphK2, have been identified. Recent identification of the conjugated bile acid-induced activation of S1PR2 as a key regulator of SphK2 opened new directions for both the sphingolipid and bile acid research fields. The role of SphKs/S1P-mediated signaling pathways in health and various human diseases has been extensively reviewed elsewhere. This review focuses on recent findings related to SphKs/S1P-medaited signaling pathways in regulating hepatic lipid metabolism.

Transforming Growth Factor β1 (TGF-β1) Appears to Promote Coronary Artery Disease by Upregulating Sphingosine Kinase 1 (SPHK1) and Further Upregulating Its Downstream TIMP-1

“…Sphingosine kinase 1, or SPHK1, catalyzes the phosphorylation of sphingosine to form sphingosine-1-phosphate (S1P) and plays pivotal roles in energy metabolism, which is crucial for the growth and survival of cells [ 19 ]. Abnormal expression of sphingosine kinase members has been proved to be involved in the regulation of cell apoptosis [ 20 , 21 ].…”

“Dicing and Splicing” Sphingosine Kinase and Relevance to Cancer

“…Recently, mice lacking SphK2 were found to have 85–90% reduction of brain S1P and impairment of contextual fear memory [ 121 ]. A breakthrough finding presented SphK2/S1PR2 signaling, not SphK1, as an important enzymatic pathway involved in regulating hepatic lipid metabolism [ 122 , 123 , 124 , 125 , 126 ]. Dysregulation of the SphK2/S1P2 signaling pathway in mice fed on a high-fat diet were more susceptible to the development of fatty liver and related diseases through regulation of conjugated bile acids, important hormones produced during the feed/fast cycle [ 126 ].…”

K27Q/K29Q mutations in sphingosine kinase 1 attenuate high-fat diet induced obesity and altered glucose homeostasis in mice

“…Sphingosine (Sph) and its metabolite sphingosine-1-phosphate (S1P) are important signaling molecules that regulate many biological processes, including differentiation, cell survival and apoptosis, angiogenesis, and inflammation 5 , 6 . S1P is formed by phosphorylation of Sph catalyzed by sphingosine kinases (Sphks), which plays central roles in sphingolipid metabolism 5 . Sphks are evolutionarily conserved and there are two mammalian isoforms (i.e.…”

“…Sphks are evolutionarily conserved and there are two mammalian isoforms (i.e. Sphk1 and Sphk2) characterized by distinct cellular localization, tissue distribution, and physiological functions 5 , 7 . Although a large number of studies have focused on the role of Sphk1 in insulin resistance and lipid metabolism, the results are controversial.…”