Abstract
Two decades ago, sphingosine 1-phosphate (S1P) was discovered as a novel bioactive molecule that regulates a variety of cellular functions. The plethora of S1P-mediated effects is due to the fact that the sphingolipid not only modulates intracellular functions but also acts as a ligand of G protein-coupled receptors after secretion into the extracellular environment. In the plasma, S1P is found in high concentrations, modulating immune cell trafficking and vascular endothelial integrity. The liver is engaged in modulating the plasma S1P content, as it produces apolipoprotein M, which is a chaperone for the S1P transport. Moreover, the liver plays a substantial role in glucose and lipid homeostasis. A dysfunction of glucose and lipid metabolism is connected with the development of liver diseases such as hepatic insulin resistance, non-alcoholic fatty liver disease, or liver fibrosis. Recent studies indicate that S1P is involved in liver pathophysiology and contributes to the development of liver diseases. In this review, the current state of knowledge about S1P and its signaling in the liver is summarized with a specific focus on the dysregulation of S1P signaling in obesity-mediated liver diseases. Thus, the modulation of S1P signaling can be considered as a potential therapeutic target for the treatment of hepatic diseases.
Highlights
Over 20 years ago, sphingosine 1-phosphate (S1P) was discovered as a novel bioactive molecule, and it is well established that S1P regulates a multitude of functions such as cell growth, survival, differentiation, migration, lymphocyte circulation, and immune cell regulation [1,2,3,4]
It has been suggested that SphK2 activation is able to increase nuclear S1P formation, which inhibits specific histone deacetylases (HDACs) causing an elevated acetylation of histones and thereby an upregulation of genes encoding nuclear receptors and enzymes involved in lipid metabolism [67]
This is in accordance with studies showing that SphK1 is inhibited after infection with bovine viral diarrhea virus (BVDV), a close relative of hepatitis C virus (HCV) [106]
Summary
Over 20 years ago, sphingosine 1-phosphate (S1P) was discovered as a novel bioactive molecule, and it is well established that S1P regulates a multitude of functions such as cell growth, survival, differentiation, migration, lymphocyte circulation, and immune cell regulation [1,2,3,4]. S1PR5 the liver, centralincluding nervous system and the spleen.fibrosis, Becauseand of the specific disease processes occur ininthe infections, cancers, metabolic receptor expression profile, S1P able complex physiological responses. Ceramides are formed through de novo novo biosynthesis or degradation of the cell membrane constituent sphingomyelin. The aldehyde can be further metabolized to palmitoyl CoA, it has been indicated that hexadecenal is an active compound that can form adducts with cellular nucleophiles such as proteins and glutathione [18,19]. It exhibits a distinguished role in the metabolism of carbohydrates, proteins, amino acids, and lipids. This review presents a brief background about the liver as a crucial organ for modulating S1P levels in the plasma, which is important for endothelial barrier function and immune cell trafficking. The divergent role of S1P in liver physiology and disease is highlighted
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