Ceramide and Sphingosine 1-Phosphate in Liver Diseases

Abstract

The liver is an important organ in the regulation of glucose and lipid metabolism. It is responsible for systemic energy homeostasis. When energy need exceeds the storage capacity in the liver, fatty acids are shunted into nonoxidative sphingolipid biosynthesis, which increases the level of cellular ceramides. Accumulation of ceramides alters substrate utilization from glucose to lipids, activates triglyceride storage, and results in the development of both insulin resistance and hepatosteatosis, increasing the likelihood of major metabolic diseases. Another sphingolipid metabolite, sphingosine 1-phosphate (S1P) is a bioactive signaling molecule that acts via S1P-specific G protein coupled receptors. It regulates many cellular and physiological events. Since an increase in plasma S1P is associated with obesity, it seems reasonable that recent studies have provided evidence that S1P is linked to lipid pathophysiology, including hepatosteatosis and fibrosis. Herein, we review recent findings on ceramides and S1P in obesity-mediated liver diseases and the therapeutic potential of these sphingolipid metabolites.

Keywords: ceramide; fibrosis; insulin resistance; obesity; sphingosine 1-phosphate; steatosis.

Fig. 1. Sphingolipid synthesis pathways and structures.

(A) Ceramide is generated by a de novo synthetic pathway and further metabolized via a salvage pathway. Once synthesized, ceramide is converted to either glucosylceramide or sphingomyelin by adding glucose or phosphocholine, respectively. Ceramide is degraded via a catabolic pathway to sphingosine is phosphorylated by sphingosine kinase (SphK), which can be degraded by S1P lyase. (B) Ceramide is synthesized by adding fatty acyl CoA to the long chain bases (sphingosine or sphinganine) and further metabolized to ceramide 1-phosphate (by phosphorylation), sphingomyelin (by adding phosphocholine), glucosylceramide (by adding glucose), and complexed glycoceramide (by adding various sugars). Ceramide is also degraded to sphingosine, which can be phosphorylated to S1P. GCS, glucosylceramide synthase; GBA, glucocerebrosidase; SMase, sphingomyelinase; SMS, sphingomyelin synthase; SPT, serine palmitoyltransferase; KDHR, 3-keto-dehydrosphingosine reductase; CerS, ceramide synthase; DES, dihydroceramide desaturase; S1P lyase, sphingosine-1-phosphate lyase; SphK, sphingosine kinase; SPP, S1P-specific phosphatases; LPP, lipid phosphate phosphatase.

Fig. 2. The roles of ceramide and S1P in liver fibrosis.

During liver fibrosis, ceramide and S1P levels are elevated. Ceramide promotes PKCζ activation, which induces CD36-mediated fatty acid uptake (Xia et al., 2015) and disturbs glucose uptake (Powell et al., 2003). Ceramide also stimulates CREB3L1 cleavage, which activates fibrogenic processes (Chen et al., 2016b; Denard et al., 2012). S1P induces Kupffer cell infiltration, which increases expressions of collagen and α-smooth muscle actin (Al Fadel et al., 2016; Friedman, 2008; Gonzalez-Fernandez et al., 2017). S1PR1 and S1PR3 is also involved in bone marrow-derived macrophage/monocytes migration to the liver (Li et al., 2011; Xiu et al., 2015). PKCζ, protein kinase C zeta; FFA, free fatty acids; CREB3L1, cAMP responsive element binding protein3 like 1; S1P, sphingosine 1-phosphate; MΦ, macrophage; αSMA, α-smooth muscle actin; S1PR, S1P receptor; BMM, bone marrow-derived macrophage/monocytes.