Mol. Cells

Ceramide and Sphingosine 1-Phosphate in Liver Diseases

Woo-Jae Park, Jae-Hwi Song, Goon-Tae Kim, and Tae-Sik Park

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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


Sphingolipid metabolism as a sensor for FA surplus

Sphingolipid metabolism is highly coordinated by a complex network of interconnected pathways, and not simply by the availability of FA substrate. The major biosynthetic site for sphingolipids is the endoplasmic reticulum (ER), where FA and amino acids are condensed to form ceramides (Fig. 1) (Merrill, 2002). The condensation of ceramide is a major branching point in the pathway; it may be used in the synthesis of S1P or converted to other complex sphingolipids including sphingomyelins and gangliosides. The enzymes converting ceramides into complex sphingolipids are localized in the Golgi apparatus. De novo synthesis of sphingolipids is initiated from condensation of serine and palmitoyl CoA by serine palmitoyltransferase (SPT) to produce 3-ketosphinganine, followed by a series of reactions involving the enzymes 3-ketosphinganine reductase, ceramide synthase (CerS), and dihydroceramide desaturase (DES) to produce ceramide. Dihydroceramides and ceramides are transported to the Golgi apparatus and used as substrates for the enzymes that synthesize complex sphingolipids. Specifically, these include sphingomyelin by sphingomyelin synthases, gangliosides by glucosylceramide synthase, and ceramide 1-phosphate by ceramide kinase.

Figure F1
(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 ...

Another important route for ceramide metabolism is generation of S1P. In this pathway, ceramide is deacylated by ceramidases to produce sphingosine. Phosphorylation of sphingosine is catalyzed by sphingosine kinases (SphK1, 2) to generate S1P. Newly synthesized S1P is transported out of the cell by an ATP-binding cassette (ABC) transporters or by a member of the major facilitator superfamily member, spinster 2 (Spxlink) (Nishi et al., 2014; Takabe and Spiegel, 2014). After export, S1P binds to one of five S1P-specific G protein coupled receptors (S1PR1-5) and activates diverse cellular responses (Maceyka and Spiegel, 2014; Pyne and Pyne, 2010). Cellular S1P levels are tightly regulated by sphingosine levels, SphKs, and the enzymes that metabolize S1P, which include S1P lyase, two S1P-specific phosphatases (SPP1-2), and three phosphate phosphatase (LPP1-3) (Maceyka et al., 2012). S1P acts as both an extracellular and intracellular signal. These have different biological functions depending on the site of generation of the SphK involved (Schwalm et al., 2013).

Ceramide is a regulatory messenger for excess FFA

A number of researchers have suggested that ceramide synthesis can be activated by increased FFAs (Samad et al., 2006; Schilling et al., 2013); and it has been suggested that ceramide synthesis regulates uptake of FFA. Uptake and esterification of FFAs are important in initiating the production and action of ceramide and overexpression of acid ceramidase in the liver reduced not only C16- and C18-ceramides but also CD36, the FA transporter (Xia et al., 2015). Overexpression of acid ceramidase also downregulated the activity of the atypical protein kinase Cζ(PKCζ), which is activated by ceramide and stimulates lipid uptake. The finding that a ceramide analogue enhanced translocation of CD36 to the membrane via a PKCζ-dependent mechanism was interpreted as evidence that ceramide regulates FA uptake and esterification. Chaurasia et al. (2019) recently demonstrated that mice deficient in DES1 were protected from hepatic steatosis. Translocation of CD36 was stimulated by ceramide in cultured hepatocytes.

Since ceramide synthesis may reduce excess FFA, it may activate esterification of FFA into TGs. Indeed, sterol response element binding proteins (SREBPs), which are major regulators of TG and cholesterol synthesis, were activated by exogenous C16-ceramides and hepatic expression of Srebf1 and its downstream targets for FA biosynthesis including FAS and FA elongation such as Elovl6 (Jiang et al., 2015). The possible mechanism implicates atypical PKCs such as PKCλ and ζ which are ceramide effectors and inducers for hepatosteatosis and hypertriglyceridemia in mice (Chen et al., 2019; Taniguchi et al., 2006). In addition, the finding that ceramide analogues inhibited isoproterenol-stimulated phosphorylation of hormone-sensitive lipase (HSL) suggested that ceramide inhibits release of FAs from TGs (Turpin et al., 2014). Collectively, these data suggest that ceramide activates TG synthesis to relieve the FFA burden and prevents FA release from lipid droplets.

Although ceramide enhanced FA entry into cells, it inhibited the uptake of glucose (Summers et al., 1998; Wang et al., 1998). The primary effect of ceramide on glucose uptake appears to be to inhibit the insulin-responsive translocation of the GLUT4 glucose transporter to the plasma membrane, by blocking insulin-mediated phosphorylation of Akt, a serine/threonine kinase involved in insulin action, anabolic signaling, and cell survival (Hajduch et al., 2001; Summers et al., 1998; Wang et al., 1998). PKCζ activated by ceramide, phosphorylates Akt on a third inhibitory site in the enzyme’s PH domain, which reduces the kinase’s affinity for phosphoinositides and prevents its PI3 kinase-dependent activation (Powell et al., 2003). In addition, ceramide-activated protein phosphatase 2A (PP2A) enhances dephosphorylation of Akt (Zinda et al., 2001). The relative contribution of either PKCζ or PP2A pathway is dependent on cell type.

Collectively, based on these findings, we suggest that ceramide regulates lipid and glucose metabolism by modulating gene expression and signaling effectors. This mechanism is the adaptation process of the substrate oxidation to adjust to lipid-overload condition.


Ceramides in hepatosteatosis

Most SM is generated by sphingomyelin synthase 1 (SMS1). Therefore, it is not surprising that SMS1-null mice exhibited moderate neonatal lethality and severe pancreatic dysfunction (Yano et al., 2011). This precludes the use of these mice in obesity experiments. Instead, mice deficient in sphingomyelin synthase (SMS 2), which are more sensitive to insulin and diet-induced obesity than WT mice (Mitsutake et al., 2011), have less PPAR-γ and its downstream target CD36, and have smaller lipid droplets. Overexpression of SMS2 in the liver had the opposite effect: it stimulated FA uptake, resulting hepatic steatosis (Li et al., 2013). Although there is a consensus that ceramide levels correlate positively with insulin resistance and development of fatty liver, SMS2 liver-specific transgenic mice had less ceramide and were more susceptible to diet-induced fatty liver formation than WT mice, while mice deficient in SMS2 had more ceramide than the WT mice and were more susceptible to diet-induced fatty liver formation. Since SMS2 is located in plasma membrane and a novel regulator of a plasma membrane microdomain, SMS2 appears to regulate FA uptake via Caveolin1 and CD36, which are also located in the microdomain (Mitsutake et al., 2011). Inhibition of glucosylceramide synthase (GCS), another enzyme that converts ceramide to glucosylceramide, also protected against HFD-induced fatty liver. These mice also had less SREBP-1c and its downstream targets, FA synthase (FAS), and stearoyl-CoA desaturase-1 (SCD-1) than mice in which GCS had not been inhibited, but PPAR-α and PPAR-γ were unaffected (Zhao et al., 2009). The exact mechanism of how GCS inhibition affects the development of fatty liver and insulin resistance is unclear, but the reduced ganglioside GM3, which plays an important role in insulin resistance (Tagami et al., 2002; Yamashita et al., 2003), could increase insulin sensitivity.

Sphingosine 1-phosphate in steatosis and obesity

The fingolimod FTY720 is a therapeutic drug for multiple sclerosis and the autoimmune disease. The drug acts as a functional antagonist of S1PR1 to induce S1PR1 degradation (Brinkmann et al., 2010). In mice fed a high-calorie diet to induce NASH, FTY720 administration reduced body and liver weight, and these effects were accompanied by decreasing hepatocyte ballooning, hepatic inflammation, and fibrosis in liver compared to mice fed a normal diet (Mauer et al., 2017). When mice fed a western diet supplemented with sweet water, the administration of FTY720 alleviated hepatosteatosis, and this was accompanied by decreasing hepatic inflammation and sphingolipid species—specifically, ceramide, dihydroceramide, S1P, and dihydro-S1P (Rohrbach et al., 2019). In contrast to mice deficient in S1PR1, the mice lacking S1PR2 rapidly developed fatty livers on a HFD (Nagahashi et al., 2015). From this evidence, it may be that the S1P receptor isotypes contribute differently to the development of fatty livers. The effects on fatty liver and insulin resistance caused by manipulation of sphingolipid levels are summarized in Table 1.

Implication of ceramides and S1P in liver fibrosis
Table 1
The effects of sphingolipids changes on fatty liver and insulin resistance

Liver fibrosis is a chronic liver disease that results from excess production of extracellular matrix proteins (Bissell, 1998), as a result of multiple injuries, functional wound healing, or chronic liver disease. It can lead to cirrhosis or liver cancer (Kisseleva et al., 2012; Kitatani et al., 2015). During fibrosis, hepatocytes undergo apoptosis and activate hepatic stellate cells by activating Kupffer cells, which release proinflammatory cytokines (Higuchi and Gores, 2003; Pessayre et al., 2002). Activated hepatic stellate cells secrete extracellular matrix to fill the space called the Disse space, and they proliferate and replace dead hepatocytes with fibrous scar tissue; this is fibrosis (Bataller and Brenner, 2005; Schuppan and Afdhal, 2008; Shea and Tager, 2012). Thus, drugs that block or inhibit hepatic stellate cell activation may be effective in preventing fibrosis (Rippe and Brenner, 2004).

Ceramide and liver fibrosis

As ceramide accumulates, cells undergo apoptosis and trigger the fibrotic events. Fibrosis is a defense mechanism to protect the tissue from lysing cells. In mice on which fibrosis was induced with carbon tetrachloride treatment, the total amount of ceramide was increased in both plasma and liver (Ichi et al., 2007), and mice lacking acid SMase had lower ceramide levels than mice with this enzyme (Mari et al., 2008). Acid sphingomyelinase activates hepatic stellate cells, which promote fibrogenesis through promoting migration of the cells and extracellular matrix secretion (Moles et al., 2010). Ceramide regulates the expression of collagen genes, important components of the extracellular matrix, via a mechanism of “regulated intra membrane proteolysis”. Cyclic AMP response element 3 like 1 (CREB3L1) is a transcriptional factor, which regulate collagen synthesis. CREB3L1 is cleaved by two Golgi-localized protease, site-1 and site-2 proteases (S1P/S2P), leading to enter the nucleus where it binds Smad4 and then upregulates transcription of genes for assembly of collagen-containing extracellular matrix (Chen et al., 2016b). Ceramides alter the orientation of TM4SF20, a protein blocking the access of S1P/S2P to CREB3L1, and activate fibrogenic processes (Chen et al., 2016b; Denard et al., 2012). In a recent study, administration of myriocin significantly reduced ceramide levels and reduced liver inflammation and fibrosis (Jiang et al., 2019). Thus, ceramide is believed to be important in regulating apoptosis of hepatocytes. It is also a potential, major target for the treatment of NASH and fibrosis.

S1P and liver fibrosis

S1P regulates the expression of various extracellular matrices during liver fibrosis (Li et al., 2009a). S1P also activates the proliferation and migration of hepatic stellate cells in vitro and increases the expression of extracellular matrix proteins, such as α-smooth muscle actin and collagen I and III (Al Fadel et al., 2016; Friedman, 2008; Gonzalez-Fernandez et al., 2017). In liver fibrosis studies, the levels of S1P were elevated consequent to increased hepatic SphK1 expression compared to the control tissue; this was observed both in fibrous liver tissue from mouse and human patients (King et al., 2017; Li et al., 2011). The expression level of Spxlink mRNA, which encodes a transporter of S1P, was elevated in fibrotic human liver compared to normal liver, indicating increased export of S1P and its binding to specific receptors, leading to fibrosis and inflammation (Sato et al., 2016). In a recent report, workers analyzed 95 patients with end-stage liver disease and observed that patients with low concentrations of plasma S1P had a poor prognosis (Becker et al., 2017). It seems, then, that S1P has a complex role in the development of advanced liver fibrosis and cirrhosis.

S1PRs and liver fibrosis

Two S1P receptors, S1PR1 and S1PR3, are considered to be the two major S1PRs that are important in liver fibrosis. Their levels were also elevated in cholestasis-induced liver fibrosis and in human fibrotic samples, whereas the S1PR2 levels were decreased, compared to the appropriate normal controls (Li et al., 2011; Xiu et al., 2015). Antagonists of S1PR1 and S1PR3 blocked upregulation of Ang1 and alleviated fibrosis in the damaged liver, whereas the S1PR2 antagonist had no effect in angiogenesis (Yang et al., 2013). Silencing of S1PR3 diminished not only the ability of bone marrow-derived cells to migrate to the liver but also their transdifferentiation into myofibroblast-like cells (Li et al., 2009a). Recently, human embryonic lethal abnormal visual protein (HuR) was induced during liver fibrosis via S1P and increased expression of S1PR3. HuR, an mRNA binding protein, affects the vitality of bone marrow-derived cells and further stabilize their mRNA (Chang et al., 2017). On the other hand, a KO mutant of S1PR2 in animal models of liver fibrosis protects mice from the development of fibrosis (Ikeda et al., 2009), and the expression of S1PR2 was reduced in the liver analysis from the patients with liver fibrosis (Li et al., 2011). We suggest that further studies are needed to identify the roles of S1P and S1PRs in the fibrosis process induced by various cells. Major sphingolipids and the mechanism for development of fatty liver and fibrosis are summarized in Fig. 2.

Therapeutic targets in the treatment and prevention of liver fibrosis
Figure F2
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., ...

Tracking and altering the signaling pathway of S1P may aid in the treatment of liver fibrosis. For example, the discovery of fingolimod, also known as FTY720 and a modulator of S1PR1, is promising. This drug has been approved by the U.S. Food and Drug Administration (FDA) and is the first oral drug that effectively treats recurrent multiple sclerosis. The development of inhibitors of S1P signaling and approaches that target enzymes in the sphingolipid pathway are novel fields in the search for efficient antifibrotic drugs (Dyckman, 2017; Park and Im, 2017). The major candidate drugs that mediate antifibrotic activity through the regulation of S1P or its receptors reported so far are summarized in Table 2.

Table 2
The candidate drugs/agents of antifibrotic activity


Ceramides are the nutrient sensors that alleviate the FFA oversupply, inhibit glucose utilization, and activate deposition of TGs in the liver. Acting independently of ceramides, S1P activates cellular signaling via S1PR binding and has important roles in hepatic pathologies. While pharmacological intervention of sphingolipid biosynthesis for NAFLD is promising, more detailed understanding of the pathways is needed. It is expected that the second generation of therapeutics for liver diseases can be pursued in light of these metabolic pathways.

Article information

Mol. Cells.May 31, 2020; 43(5): 419-430.
Published online 2020-05-12. doi:  10.14348/molcells.2020.0054
1Department of Biochemistry, College of Medicine, Gachon University, Incheon 2999, Korea
2Department of Life Science, Gachon University, Seongnam 1310, Korea
*Correspondence: (WJP); (TSP)
Received March 1, 2020; Accepted April 19, 2020.
Articles from Mol. Cells are provided here courtesy of Mol. Cells


  • Aerts, J.M., Ottenhoff, R., Powlson, A.S., Grefhorst, A., van Eijk, M., Dubbelhuis, P.F., Aten, J., Kuipers, F., Serlie, M.J., and Wennekes, T. (2007). Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes. 56, 1341-1349.
  • Al Fadel, F., Fayyaz, S., Japtok, L., and Kleuser, B. (2016). Involvement of sphingosine 1-phosphate in palmitate-induced non-alcoholic fatty liver disease. Cell. Physiol. Biochem.. 40, 1637-1645.
  • Barr, E.L., Cameron, A.J., Balkau, B., Zimmet, P.Z., Welborn, T.A., Tonkin, A.M., and Shaw, J.E. (2010). HOMA insulin sensitivity index and the risk of all-cause mortality and cardiovascular disease events in the general population: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) study. Diabetologia. 53, 79-88.
  • Bashiardes, S., Shapiro, H., Rozin, S., Shibolet, O., and Elinav, E. (2016). Non-alcoholic fatty liver and the gut microbiota. Mol. Metab.. 5, 782-794.
  • Bataller, R. and Brenner, D.A. (2005). Liver fibrosis. J. Clin. Invest.. 115, 209-218.
  • Becker, S., Kinny-Koster, B., Bartels, M., Scholz, M., Seehofer, D., Berg, T., Engelmann, C., Thiery, J., Ceglarek, U., and Kaiser, T. (2017). Low sphingosine-1-phosphate plasma levels are predictive for increased mortality in patients with liver cirrhosis. PLoS One. 12, .
  • Bissell, D.M. (1998). Hepatic fibrosis as wound repair: a progress report. J. Gastroenterol.. 33, 295-302.
  • Bradbury, M.W. (2006). Lipid metabolism and liver inflammation. I. Hepatic fatty acid uptake: possible role in steatosis. Am. J. Physiol. Gastrointest. Liver Physiol.. 290, G194-G198.
  • Brinkmann, V., Billich, A., Baumruker, T., Heining, P., Schmouder, R., Francis, G., Aradhye, S., and Burtin, P. (2010). Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov.. 9, 883-897.
  • Brunati, A.M., Tibaldi, E., Carraro, A., Gringeri, E., D'Amico, F., Toninello, A., Massimino, M.L., Pagano, M.A., Nalesso, G., and Cillo, U. (2008). Cross-talk between PDGF and S1P signalling elucidates the inhibitory effect and potential antifibrotic action of the immunomodulator FTY720 in activated HSC-cultures. Biochim. Biophys. Acta. 1783, 347-359.
  • Chang, N., Ge, J., Xiu, L., Zhao, Z., Duan, X., Tian, L., Xie, J., Yang, L., and Li, L. (2017). HuR mediates motility of human bone marrow-derived mesenchymal stem cells triggered by sphingosine 1-phosphate in liver fibrosis. J. Mol. Med.. 95, 69-82.
  • Chaurasia, B., Tippetts, T.S., Mayoral Monibas, R., Liu, J., Li, Y., Wang, L., Wilkerson, J.L., Sweeney, C.R., and Pereira, R.F. (2019). Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science. 365, 386-392.
  • Chen, J., Wang, W., Qi, Y., Kaczorowski, D., McCaughan, G.W., Gamble, J.R., Don, A.S., Gao, X., Vadas, M.A., and Xia, P. (2016a). Deletion of sphingosine kinase 1 ameliorates hepatic steatosis in diet-induced obese mice: role of PPARγ. Biochim. Biophys. Acta. 1861, 138-147.
  • Chen, Q., Denard, B., Lee, C.E., Han, S., Ye, J.S., and Ye, J. (2016b). Inverting the topology of a transmembrane protein by regulating the translocation of the first transmembrane helix. Mol. Cell. 63, 567-578.
  • Chen, T.C., Lee, R.A., Tsai, S.L., Kanamaluru, D., Gray, N.E., Yiv, N., Cheang, R.T., Tan, J.H., Lee, J.Y., and Fitch, M.D. (2019). An ANGPTL4-ceramide-protein kinase Czeta axis mediates chronic glucocorticoid exposure-induced hepatic steatosis and hypertriglyceridemia in mice. J. Biol. Chem.. 294, 9213-9224.
  • Cohen, J.C., Horton, J.D., and Hobbs, H.H. (2011). Human fatty liver disease: old questions and new insights. Science. 332, 1519-1523.
  • Deevska, G.M., Rozenova, K.A., Giltiay, N.V., Chambers, M.A., White, J., Boyanovsky, B.B., Wei, J., Daugherty, A., Smart, E.J., and Reid, M.B. (2009). Acid sphingomyelinase deficiency prevents diet-induced hepatic triacylglycerol accumulation and hyperglycemia in mice. J. Biol. Chem.. 284, 8359-8368.
  • Denard, B., Lee, C., and Ye, J. (2012). Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1. Elife. 1, .
  • Ding, B.S., Liu, C.H., Sun, Y., Chen, Y., Swendeman, S.L., Jung, B., Chavez, D., Cao, Z., Christoffersen, C., and Nielsen, L.B. (2016). HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) promotes regeneration and suppresses fibrosis in the liver. JCI Insight. 1, .
  • Dyckman, A.J. (2017). Modulators of sphingosine-1-phosphate pathway biology: recent advances of sphingosine-1-phosphate receptor 1 (S1P1) agonists and future perspectives. J. Med. Chem.. 60, 5267-5289.
  • Friedman, S.L. (2008). Mechanisms of hepatic fibrogenesis. Gastroenterology. 134, 1655-1669.
  • Fucho, R., Martínez, L., Baulies, A., Torres, S., Tarrats, N., Fernández, A., Ribas, V., Astudillo, A.M., Balsinde, J., and Garcia-Rovés, P. (2014). ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis. J. Hepatol.. 61, 1126-1134.
  • Gao, D., Pararasa, C., Dunston, C.R., Bailey, C.J., and Griffiths, H.R. (2012). Palmitate promotes monocyte atherogenicity via de novo ceramide synthesis. Free Radic. Biol. Med.. 53, 796-806.
  • Gao, W., Liu, H., Yuan, J., Wu, C., Huang, D., Ma, Y., Zhu, J., Ma, L., Guo, J., and Shi, H. (2016). Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF-α mediated NF-κB pathway. J. Cell. Mol. Med.. 20, 2318-2327.
  • Geng, T., Sutter, A., Harland, M.D., Law, B.A., Ross, J.S., Lewin, D., Palanisamy, A., Russo, S.B., Chavin, K.D., and Cowart, L.A. (2015). SphK1 mediates hepatic inflammation in a mouse model of NASH induced by high saturated fat feeding and initiates proinflammatory signaling in hepatocytes. J. Lipid Res.. 56, 2359-2371.
  • Gonzalez-Fernandez, B., Sanchez, D.I., Crespo, I., San-Miguel, B., Alvarez, M., Tunon, M.J., and Gonzalez-Gallego, J. (2017). Inhibition of the SphK1/S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells. BioFactors. 43, 272-282.
  • Gosejacob, D., Jäger, P.S., Vom Dorp, K., Frejno, M., Carstensen, A.C., Köhnke, M., Degen, J., Dörmann, P., and Hoch, M. (2016). Ceramide synthase 5 is essential to maintain C16:0-ceramide pools and contributes to the development of diet-induced obesity. J. Biol. Chem.. 291, 6989-7003.
  • Hajduch, E., Balendran, A., Batty, I.H., Litherland, G.J., Blair, A.S., Downes, C.P., and Hundal, H.S. (2001). Ceramide impairs the insulin-dependent membrane recruitment of protein kinase B leading to a loss in downstream signalling in L6 skeletal muscle cells. Diabetologia. 44, 173-183.
  • Hastie, C.E., Padmanabhan, S., Slack, R., Pell, A.C., Oldroyd, K.G., Flapan, A.D., Jennings, K.P., Irving, J., Eteiba, H., and Dominiczak, A.F. (2010). Obesity paradox in a cohort of 4880 consecutive patients undergoing percutaneous coronary intervention. Eur. Heart J.. 31, 222-226.
  • Higuchi, H. and Gores, G.J. (2003). Mechanisms of liver injury: an overview. Curr. Mol. Med.. 3, 483-490.
  • Holland, W.L., Brozinick, J.T., Wang, L.P., Hawkins, E.D., Sargent, K.M., Liu, Y., Narra, K., Hoehn, K.L., Knotts, T.A., and Siesky, A. (2007). Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab.. 5, 167-179.
  • Ichi, I., Nakahara, K., Fujii, K., Iida, C., Miyashita, Y., and Kojo, S. (2007). Increase of ceramide in the liver and plasma after carbon tetrachloride intoxication in the rat. J. Nutr. Sci. Vitaminol.. 53, 53-56.
  • Ikeda, H., Watanabe, N., Ishii, I., Shimosawa, T., Kume, Y., Tomiya, T., Inoue, Y., Nishikawa, T., Ohtomo, N., and Tanoue, Y. (2009). Sphingosine 1-phosphate regulates regeneration and fibrosis after liver injury via sphingosine 1-phosphate receptor 2. J. Lipid Res.. 50, 556-564.
  • Jiang, C., Xie, C., Li, F., Zhang, L., Nichols, R.G., Krausz, K.W., Cai, J., Qi, Y., Fang, Z.Z., and Takahashi, S. (2015). Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J. Clin. Invest.. 125, 386-402.
  • Jiang, M., Li, C., Liu, Q., Wang, A., and Lei, M. (2019). Inhibiting ceramide synthesis attenuates hepatic steatosis and fibrosis in rats with non-alcoholic fatty liver disease. Front. Endocrinol.. 10, 665.
  • Jin, J., Zhang, X., Lu, Z., Perry, D.M., Li, Y., Russo, S.B., Cowart, L.A., Hannun, Y.A., and Huang, Y. (2013). Acid sphingomyelinase plays a key role in palmitic acid-amplified inflammatory signaling triggered by lipopolysaccharide at low concentrations in macrophages. Am. J. Physiol. Endocrinol. Metab.. 305, E853-E867.
  • Kageyama, Y., Ikeda, H., Watanabe, N., Nagamine, M., Kusumoto, Y., Yashiro, M., Satoh, Y., Shimosawa, T., Shinozaki, K., and Tomiya, T. (2012). Antagonism of sphingosine 1-phosphate receptor 2 causes a selective reduction of portal vein pressure in bile duct-ligated rodents. Hepatology. 56, 1427-1438.
  • Kaneko, T., Murakami, T., Kawana, H., Takahashi, M., Yasue, T., and Kobayashi, E. (2006). Sphingosine-1-phosphate receptor agonists suppress concanavalin A-induced hepatic injury in mice. Biochem. Biophys. Res. Commun.. 345, 85-92.
  • Khattar, M., Deng, R., Kahan, B.D., Schroder, P.M., Phan, T., Rutzky, L.P., and Stepkowski, S.M. (2013). Novel sphingosine-1-phosphate receptor modulator KRP203 combined with locally delivered regulatory T cells induces permanent acceptance of pancreatic islet allografts. Transplantation. 95, 919-927.
  • Kim, Y.R., Lee, E.J., Shin, K.O., Kim, M.H., Pewzner-Jung, Y., Lee, Y.M., Park, J.W., Futerman, A.H., and Park, W.J. (2019). Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases. Exp. Mol. Med.. 51, 1-16.
  • King, A., Houlihan, D.D., Kavanagh, D., Haldar, D., Luu, N., Owen, A., Suresh, S., Than, N.N., Reynolds, G., and Penny, J. (2017). Sphingosine-1-phosphate prevents egress of hematopoietic stem cells from liver to reduce fibrosis. Gastroenterology. 153, 233-248.
  • Kisseleva, T., Cong, M., Paik, Y., Scholten, D., Jiang, C., Benner, C., Iwaisako, K., Moore-Morris, T., Scott, B., and Tsukamoto, H. (2012). Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc. Natl. Acad. Sci. U. S. A.. 109, 9448-9453.
  • Kitatani, K., Taniguchi, M., and Okazaki, T. (2015). Role of sphingolipids and metabolizing enzymes in hematological malignancies. Mol. Cells. 38, 482-495.
  • Kong, Y., Wang, H., Wang, S., and Tang, N. (2014). FTY720, a sphingosine-1 phosphate receptor modulator, improves liver fibrosis in a mouse model by impairing the motility of bone marrow-derived mesenchymal stem cells. Inflammation. 37, 1326-1336.
  • Kowalski, G.M., Kloehn, J., Burch, M.L., Selathurai, A., Hamley, S., Bayol, S.A.M., Lamon, S., Watt, M.J., Lee-Young, R.S., and McConville, M.J. (2015). Overexpression of sphingosine kinase 1 in liver reduces triglyceride content in mice fed a low but not high-fat diet. Biochim. Biophys. Acta. 1851, 210-219.
  • Kurek, K., Piotrowska, D.M., Wiesiołek, P., Lukaszuk, B., Chabowski, A., Górski, J., and Żendzian-Piotrowska, M. (2013). Inhibition of ceramide de novo synthesis reduces liver lipid accumulation in rats with nonalcoholic fatty liver disease. Liver Int.. 34, 1074-1083.
  • Lallemand, T., Rouahi, M., Swiader, A., Grazide, M.H., Geoffre, N., Alayrac, P., Recazens, E., Coste, A., Salvayre, R., and Nègre-Salvayre, A. (2018). nSMase2 (type 2-neutral sphingomyelinase) deficiency or inhibition by GW4869 reduces inflammation and atherosclerosis in Apoe-/- mice. Arterioscler. Thromb. Vasc. Biol.. 38, 1479-1492.
  • Lee, S.Y., Hong, I.K., Kim, B.R., Shim, S.M., Lee, J.S., Lee, H.Y., Choi, C.S., Kim, B.K., and Park, T.S. (2015). Activation of sphingosine kinase 2 by endoplasmic reticulum stress ameliorates hepatic steatosis and insulin resistance in mice. Hepatology. 62, 135-146.
  • Li, C., Jiang, X., Yang, L., Liu, X., Yue, S., and Li, L. (2009a). Involvement of sphingosine 1-phosphate (SIP)/S1P3 signaling in cholestasis-induced liver fibrosis. Am. J. Pathol.. 175, 1464-1472.
  • Li, C., Kong, Y., Wang, H., Wang, S., Yu, H., Liu, X., Yang, L., Jiang, X., Li, L., and Li, L. (2009b). Homing of bone marrow mesenchymal stem cells mediated by sphingosine 1-phosphate contributes to liver fibrosis. J. Hepatol.. 50, 1174-1183.
  • Li, C., Zheng, S., You, H., Liu, X., Lin, M., Yang, L., and Li, L. (2011). Sphingosine 1-phosphate (S1P)/S1P receptors are involved in human liver fibrosis by action on hepatic myofibroblasts motility. J. Hepatol.. 54, 1205-1213.
  • Li, Y., Dong, J., Ding, T., Kuo, M.S., Cao, G., Jiang, X.C., and Li, Z. (2013). Sphingomyelin synthase 2 activity and liver steatosis: an effect of ceramide-mediated peroxisome proliferator-activated receptor γ2 suppression. Arterioscler. Thromb. Vasc. Biol.. 33, 1513-1520.
  • Liangpunsakul, S., Rahmini, Y., Ross, R.A., Zhao, Z., Xu, Y., and Crabb, D.W. (2012). Imipramine blocks ethanol-induced ASMase activation, ceramide generation, and PP2A activation, and ameliorates hepatic steatosis in ethanol-fed mice. Am. J. Physiol. Gastrointest. Liver Physiol.. 302, G515-G523.
  • Lindenmeyer, C.C. and McCullough, A.J. (2018). The natural history of nonalcoholic fatty liver disease-an evolving view. Clin. Liver Dis.. 22, 11-21.
  • Liu, X., Yue, S., Li, C., Yang, L., You, H., and Li, L. (2011). Essential roles of sphingosine 1-phosphate receptor types 1 and 3 in human hepatic stellate cells motility and activation. J. Cell. Physiol.. 226, 2370-2377.
  • Longato, L., Tong, M., Wands, J.R., and de la Monte, S.M. (2012). High fat diet induced hepatic steatosis and insulin resistance: role of dysregulated ceramide metabolism. Hepatol. Res.. 42, 412-427.
  • Ma, M.M., Chen, J.L., Wang, G.G., Wang, H., Lu, Y., Li, J.F., Yi, J., Yuan, Y.J., Zhang, Q.W., and Mi, J. (2007). Sphingosine kinase 1 participates in insulin signalling and regulates glucose metabolism and homeostasis in KK/Ay diabetic mice. Diabetologia. 50, 891-900.
  • Maceyka, M., Harikumar, K.B., Milstien, S., and Spiegel, S. (2012). Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol.. 22, 50-60.
  • Maceyka, M. and Spiegel, S. (2014). Sphingolipid metabolites in inflammatory disease. Nature. 510, 58-67.
  • Mari, M., Colell, A., Morales, A., Caballero, F., Moles, A., Fernandez, A., Terrones, O., Basanez, G., Antonsson, B., and Garcia-Ruiz, C. (2008). Mechanism of mitochondrial glutathione-dependent hepatocellular susceptibility to TNF despite NF-kappaB activation. Gastroenterology. 134, 1507-1520.
  • Mauer, A.S., Hirsova, P., Maiers, J.L., Shah, V.H., and Malhi, H. (2017). Inhibition of sphingosine 1-phosphate signaling ameliorates murine nonalcoholic steatohepatitis. Am. J. Physiol. Gastrointest. Liver Physiol.. 312, G300-G313.
  • Merrill, A.H. (2002). De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J. Biol. Chem.. 277, 25843-25846.
  • Mitsutake, S., Zama, K., Yokota, H., Yoshida, T., Tanaka, M., Mitsui, M., Ikawa, M., Okabe, M., Tanaka, Y., and Yamashita, T. (2011). Dynamic modification of sphingomyelin in lipid microdomains controls development of obesity, fatty liver, and type 2 diabetes. J. Biol. Chem.. 286, 28544-28555.
  • Moles, A., Tarrats, N., Morales, A., Domínguez, M., Bataller, R., Caballería, J., Garcia-Ruiz, C., Fernandez-Checa, J.C., and Mari, M. (2010). Acidic sphingomyelinase controls hepatic stellate cell activation and in vivo liver fibrogenesis. Am. J. Pathol.. 177, 1214-1224.
  • Nagahashi, M., Takabe, K., Liu, R., Peng, K., Wang, X., Wang, Y., Hait, N.C., Wang, X., Allegood, J.C., and Yamada, A. (2015). Conjugated bile acid-activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression. Hepatology. 61, 1216-1226.
  • Nishi, T., Kobayashi, N., Hisano, Y., Kawahara, A., and Yamaguchi, A. (2014). Molecular and physiological functions of sphingosine 1-phosphate transporters. Biochim. Biophys. Acta. 1841, 759-765.
  • Park, S.J. and Im, D.S. (2017). Sphingosine 1-phosphate receptor modulators and drug discovery. Biomol. Ther.. 25, 80-90.
  • Park, W.J., Park, J.W., Merrill, A.H., Storch, J., Pewzner-Jung, Y., and Futerman, A.H. (2014). Hepatic fatty acid uptake is regulated by the sphingolipid acyl chain length. Biochim. Biophys. Acta. 1841, 1754-1766.
  • Pessayre, D., Mansouri, A., and Fromenty, B. (2002). Nonalcoholic steatosis and steatohepatitis. V. Mitochondrial dysfunction in steatohepatitis. Am. J. Physiol. Gastrointest. Liver Physiol.. 282, G193-G199.
  • Postic, C. and Girard, J. (2008). Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J. Clin. Invest.. 118, 829-838.
  • Powell, D.J., Hajduch, E., Kular, G., and Hundal, H.S. (2003). Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCzeta-dependent mechanism. Mol. Cell. Biol.. 23, 7794-7808.
  • Pyne, N.J. and Pyne, S. (2010). Sphingosine 1-phosphate and cancer. Nat. Rev. Cancer. 10, 489-503.
  • Qi, Y., Chen, J., Lay, A., Don, A., Vadas, M., and Xia, P. (2013). Loss of sphingosine kinase 1 predisposes to the onset of diabetes via promoting pancreatic β-cell death in diet-induced obese mice. FASEB J.. 27, 4294-4304.
  • Raichur, S., Wang, S.T., Chan, P.W., Li, Y., Ching, J., Chaurasia, B., Dogra, S., Öhman, M.K., Takeda, K., and Sugii, S. (2014). CerS2 haploinsufficiency inhibits β-Oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab.. 20, 687-695.
  • Rinella, M.E. and Sanyal, A.J. (2016). Management of NAFLD: a stage-based approach. Nat. Rev. Gastroenterol. Hepatol.. 13, 196-205.
  • Rippe, R.A. and Brenner, D.A. (2004). From quiescence to activation: gene regulation in hepatic stellate cells. Gastroenterology. 127, 1260-1262.
  • Rohrbach, T., Maceyka, M., and Spiegel, S. (2017). Sphingosine kinase and sphingosine-1-phosphate in liver pathobiology. Crit. Rev. Biochem. Mol. Biol.. 52, 543-553.
  • Rohrbach, T.D., Asgharpour, A., Maczis, M.A., Montefusco, D., Cowart, L.A., Bedossa, P., Sanyal, A.J., and Spiegel, S. (2019). FTY720/fingolimod decreases hepatic steatosis and expression of fatty acid synthase in diet-induced nonalcoholic fatty liver disease in mice. J. Lipid Res.. 60, 1311-1322.
  • Rutkute, K., Asmis, R.H., and Nikolova-Karakashian, M.N. (2007a). Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation. J. Lipid Res.. 48, 2443-2452.
  • Rutkute, K., Karakashian, A.A., Giltiay, N.V., Dobierzewska, A., and Nikolova-Karakashian, M.N. (2007b). Aging in rat causes hepatic hyperresposiveness to interleukin-1beta which is mediated by neutral sphingomyelinase-2. Hepatology. 46, 1166-1176.
  • Samad, F., Hester, K.D., Yang, G., Hannun, Y.A., and Bielawski, J. (2006). Altered adipose and plasma sphingolipid metabolism in obesity: a potential mechanism for cardiovascular and metabolic risk. Diabetes. 55, 2579-2587.
  • Sanyal, A.J. and Pacana, T. (2015). A lipidomic readout of disease progression in a diet-induced mouse model of nonalcoholic fatty liver disease. Trans. Am. Clin. Climatol. Assoc.. 126, 271-288.
  • Sato, M., Ikeda, H., Uranbileg, B., Kurano, M., Saigusa, D., Aoki, J., Maki, H., Kudo, H., Hasegawa, K., and Kokudo, N. (2016). Sphingosine kinase-1, S1P transporter spinster homolog 2 and S1P2 mRNA expressions are increased in liver with advanced fibrosis in human. Sci. Rep.. 6, 32119.
  • Sattar, N., Forrest, E., and Preiss, D. (2014). Non-alcoholic fatty liver disease. BMJ. 349, g4596.
  • Schilling, J.D., Machkovech, H.M., He, L., Sidhu, R., Fujiwara, H., Weber, K., Ory, D.S., and Schaffer, J.E. (2013). Palmitate and lipopolysaccharide trigger synergistic ceramide production in primary macrophages. J. Biol. Chem.. 288, 2923-2932.
  • Schuppan, D. and Afdhal, N.H. (2008). Liver cirrhosis. Lancet. 371, 838-851.
  • Schwalm, S., Pfeilschifter, J., and Huwiler, A. (2013). Sphingosine-1-phosphate: a Janus-faced mediator of fibrotic diseases. Biochim. Biophys. Acta. 1831, 239-250.
  • Shea, B.S. and Tager, A.M. (2012). Sphingolipid regulation of tissue fibrosis. Open Rheumatol. J.. 6, 123-129.
  • Stoffel, W., Jenke, B., Holz, B., Binczek, E., Günter, R.H., Knifka, J., Koebke, J., and Niehoff, A. (2007). Neutral sphingomyelinase (SMPD3) deficiency causes a novel form of chondrodysplasia and dwarfism that is rescued by Col2A1-driven smpd3 transgene expression. Am. J. Pathol.. 171, 153-161.
  • Summers, S.A., Garza, L.A., Zhou, H., and Birnbaum, M.J. (1998). Regulation of insulin-stimulated glucose transporter GLUT4 translocation and Akt kinase activity by ceramide. Mol. Cell. Biol.. 18, 5457-5464.
  • Tagami, S., Inokuchi Ji, J., Kabayama, K., Yoshimura, H., Kitamura, F., Uemura, S., Ogawa, C., Ishii, A., Saito, M., and Ohtsuka, Y. (2002). Ganglioside GM3 participates in the pathological conditions of insulin resistance. J. Biol. Chem.. 277, 3085-3092.
  • Takabe, K. and Spiegel, S. (2014). Export of sphingosine-1-phosphate and cancer progression. J. Lipid Res.. 55, 1839-1846.
  • Taniguchi, C.M., Kondo, T., Sajan, M., Luo, J., Bronson, R., Asano, T., Farese, R., Cantley, L.C., and Kahn, C.R. (2006). Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. Cell Metab.. 3, 343-353.
  • Turner, N., Kowalski, G.M., Leslie, S.J., Risis, S., Yang, C., Lee-Young, R.S., Babb, J.R., Meikle, P.J., Lancaster, G.I., and Henstridge, D.C. (2013). Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding. Diabetologia. 56, 1638-1648.
  • Turpin, S.M., Nicholls, H.T., Willmes, D.M., Mourier, A., Brodesser, S., Wunderlich, C.M., Mauer, J., Xu, E., Hammerschmidt, P., and Brönneke, H.S. (2014). Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab.. 20, 678-686.
  • Unger, R.H. (2003). Lipid overload and overflow: metabolic trauma and the metabolic syndrome. Trends Endocrinol. Metab.. 14, 398-403.
  • Ussher, J.R., Koves, T.R., Cadete, V.J.J., Zhang, L., Jaswal, J.S., Swyrd, S.J., Lopaschuk, D.G., Proctor, S.D., Keung, W., and Muoio, D.M. (2010). Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes. 59, 2453-2464.
  • Verma, M.K., Yateesh, A.N., Neelima, K., Pawar, N., Sandhya, K., Poornima, J., Lakshmi, M.N., Yogeshwari, S., Pallavi, P.M., and Oommen, A.M. (2014). Inhibition of neutral sphingomyelinases in skeletal muscle attenuates fatty-acid induced defects in metabolism and stress. SpringerPlus. 3, 255-212.
  • Wang, C.N., O'Brien, L., and Brindley, D.N. (1998). Effects of cell-permeable ceramides and tumor necrosis factor-alpha on insulin signaling and glucose uptake in 3T3-L1 adipocytes. Diabetes. 47, 24-31.
  • Wang, R., Ding, Q., De Assuncao, T.M., Mounajjed, T., Maiers, J.L., Dou, C., Cao, S., Yaqoob, U., Huebert, R.C., and Shah, V.H. (2017a). Hepatic stellate cell selective disruption of dynamin-2 GTPase increases murine fibrogenesis through up-regulation of sphingosine-1 phosphate-induced cell migration. Am. J. Pathol.. 187, 134-145.
  • Wang, Y., Harashima, S.I., Liu, Y., Usui, R., and Inagaki, N. (2017b). Sphingosine kinase 1-interacting protein is a novel regulator of glucose-stimulated insulin secretion. Sci. Rep.. 7, 779.
  • Watt, M.J., Barnett, A.C., Bruce, C.R., Schenk, S., Horowitz, J.F., and Hoy, A.J. (2012). Regulation of plasma ceramide levels with fatty acid oversupply: evidence that the liver detects and secretes de novo synthesised ceramide. Diabetologia. 55, 2741-2746.
  • Xia, J.Y., Holland, W.L., Kusminski, C.M., Sun, K., Sharma, A.X., Pearson, M.J., Sifuentes, A.J., McDonald, J.G., Gordillo, R., and Scherer, P.E. (2015). Targeted induction of ceramide degradation leads to improved systemic metabolism and reduced hepatic steatosis. Cell Metab.. 22, 266-278.
  • Xiu, L., Chang, N., Yang, L., Liu, X., Yang, L., Ge, J., and Li, L. (2015). Intracellular sphingosine 1-phosphate contributes to collagen expression of hepatic myofibroblasts in human liver fibrosis independent of its receptors. Am. J. Pathol.. 185, 387-398.
  • Xu, W., Lu, C., Zhang, F., Shao, J., and Zheng, S. (2016). Dihydroartemisinin restricts hepatic stellate cell contraction via an FXR-S1PR2-dependent mechanism. IUBMB Life. 68, 376-387.
  • Yamashita, T., Hashiramoto, A., Haluzik, M., Mizukami, H., Beck, S., Norton, A., Kono, M., Tsuji, S., Daniotti, J.L., and Werth, N. (2003). Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc. Natl. Acad. Sci. U. S. A.. 100, 3445-3449.
  • Yang, G., Badeanlou, L., Bielawski, J., Roberts, A.J., Hannun, Y.A., and Samad, F. (2009). Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome. Am. J. Physiol. Endocrinol. Metab.. 297, E211-E224.
  • Yang, L., Chang, N., Liu, X., Han, Z., Zhu, T., Li, C., Yang, L., and Li, L. (2012). Bone marrow-derived mesenchymal stem cells differentiate to hepatic myofibroblasts by transforming growth factor-beta1 via sphingosine kinase/sphingosine 1-phosphate (S1P)/S1P receptor axis. Am. J. Pathol.. 181, 85-97.
  • Yang, L., Han, Z., Tian, L., Mai, P., Zhang, Y., Wang, L., and Li, L. (2015). Sphingosine 1-phosphate receptor 2 and 3 mediate bone marrow-derived monocyte/macrophage motility in cholestatic liver injury in mice. Sci. Rep.. 5, 13423.
  • Yang, L., Yue, S., Yang, L., Liu, X., Han, Z., Zhang, Y., and Li, L. (2013). Sphingosine kinase/sphingosine 1-phosphate (S1P)/S1P receptor axis is involved in liver fibrosis-associated angiogenesis. J. Hepatol.. 59, 114-123.
  • Yano, M., Watanabe, K., Yamamoto, T., Ikeda, K., Senokuchi, T., Lu, M., Kadomatsu, T., Tsukano, H., Ikawa, M., and Okabe, M. (2011). Mitochondrial dysfunction and increased reactive oxygen species impair insulin secretion in sphingomyelin synthase 1-null mice. J. Biol. Chem.. 286, 3992-4002.
  • Ying, W., Riopel, M., Bandyopadhyay, G., Dong, Y., Birmingham, A., Seo, J.B., Ofrecio, J.M., Wollam, J., Hernandez-Carretero, A., and Fu, W. (2017). Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell. 171, 372-384.
  • Younossi, Z.M., Koenig, A.B., Abdelatif, D., Fazel, Y., Henry, L., and Wymer, M. (2016). Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 64, 73-84.
  • Zhao, H., Przybylska, M., Wu, I.H., Zhang, J., Maniatis, P., Pacheco, J., Piepenhagen, P., Copeland, D., Arbeeny, C., and Shayman, J.A. (2009). Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice. Hepatology. 50, 85-93.
  • Zhao, H., Przybylska, M., Wu, I.H., Zhang, J., Siegel, C., Komarnitsky, S., Yew, N.S., and Cheng, S.H. (2007). Inhibiting glycosphingolipid synthesis improves glycemic control and insulin sensitivity in animal models of type 2 diabetes. Diabetes. 56, 1210-1218.
  • Zigdon, H., Kogot-Levin, A., Park, J.W., Goldschmidt, R., Kelly, S., Merrill, A.H., Scherz, A., Pewzner-Jung, Y., Saada, A., and Futerman, A.H. (2013). Ablation of ceramide synthase 2 causes chronic oxidative stress due to disruption of the mitochondrial respiratory chain. J. Biol. Chem.. 288, 4947-4956.
  • Zinda, M.J., Vlahos, C.J., and Lai, M.T. (2001). Ceramide induces the dephosphorylation and inhibition of constitutively activated Akt in PTEN negative U87mg cells. Biochem. Biophys. Res. Commun.. 280, 1107-1115.

Figure 1

(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.

Figure 2

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.

Table 1

The effects of sphingolipids changes on fatty liver and insulin resistance

Pathway Chemical treated or KO mice Insulin resistance Fatty liver Phenotype Reference
De novo ceramide biosynthesis Myriocin Improved Improved Weight gain after HFD ↓ Serum ceramide ↓ Insulin signaling in liver and muscle ↑ Energy expenditure ↑ (UCP3 ↑, SOCS-3 ↓ in adipose tissue) ( Holland et al., 2007; Kurek et al., 2013; Ussher et al., 2010; Yang et al., 2009)
DES1 KO mice Improved Improved Weight gain in ob/ob mice ↓ Hepatic C16, C18, C20, C22, C24-Cer ↓ Serum C16, C18, C20, C22, C24-Cer ↓ White adipose tissue mass ↓ ( Chaurasia et al., 2019)
CerS6 KO mice Improved Improved Weight gain after HFD ↓ Hepatic p-Akt, p-GSK3 ↑ Energy expenditure ↑ β-oxidation capacity in brown adipose tissue ↑ Hepatic β-oxidation ↑ PPAR-γ, CD36 ↓ ( Turpin et al., 2014)
CerS5 KO mice Improved Improved Weight gain after HFD ↓ ( Gosejacob et al., 2016)
CerS2 heterozygote (+/–) mice Aggravated Aggravated Serum cholesterol ↑ γImpaired lipid oxidation γImparted electron transport chain activity ( Raichur et al., 2014)
Salvage pathway nSMase2 KO mice No study No study Dwarfism phenotype Joint deformation Short statured long bones Growth hormone ↓ ( Stoffel et al., 2007)
aSMase KO mice Improved Improved Hepatic stellate cells proliferation ↓ Liver fibrosis after bile duct ligation ↓ ER stress ↓ ( Fucho et al., 2014)
aSMase inhibition (amitrypsine, imipramine, desipramine) Improved Improved Inflammation ↓ Serum ceramide ↓ C16-Cer, C24-Cer ↓ p-Akt, p-p70S6K ↑ p-p38, p-JNK ↓ ( Fucho et al., 2014; Jin et al., 2013; Liangpunsakul et al., 2012)
GCS inhibition (Genz-123346, Genz-112638, AMP-DNM) Improved Improved FAS, SCD-1, ACC1 ↓ p-Insulin receptor-β, p-mTOR ↑ GM3 ↓ ( Aerts et al., 2007; Zhao et al., 2007; 2009)
Sphingomyelin pathway SMS1 KO mice No study No study Mitochondrial dysfunction Impaired insulin secretion ( Yano et al., 2011)
SMS2 KO mice Improved Improved Weight gain after HFD ↓ PPAR-γ, CD36 ↓ ( Mitsutake et al., 2011)
SMS2 transgenic mice No study Aggravated CD36 ↑ ( Li et al., 2013)
Catabolic pathway SphK1 null mice Aggravated Improved Hepatic triglyceride, cholesterol ↓ Hepatic S1P ↓ PPAR-γ, CD36, UCP2, Cidea ↓ Pancreatic β-cell mass in HFD-fed ↓ Insulin production in HFD-fed ↓ ( Chen et al., 2016a; Qi et al., 2013)
SphK1 overexpression by AdSphK1 Improved Improved Hepatic triglyceride ↓ p-Akt, p-GSK3 ↑ ( Ma et al., 2007)
SphK2 overexpression by AdSphK2 Improved Improved p-Akt ↑ C16, C18, C24:1-Cer ↓ Sphingosine, sphinganine ↓ PPAR-α, CPT1, ACOX1 ↑ ( Lee et al., 2015)
FTY720 (S1PR1 antagonist) Improved Improved Macrophage infiltration ↓ Ly6-C (monocyte-derived macrophages marker), CCR2 (C-C chemokine receptor type 2) ↓ α-smooth muscle actin ↓ C16-, C24:1-ceramide ↓ Fatty acid synthase ↓ S1P, dihydro-S1P ↓ ( Mauer et al., 2017; Rohrbach et al., 2019)
S1PR2 deficiency mice No study Aggravated H3K9 acetylation ↓ H4K5 acetylation ↓ H2BK12 acetylation ↓ ( Nagahashi et al., 2015)

Table 2

The candidate drugs/agents of antifibrotic activity

Action Drug/agent Reference
Sphingosine kinase inhibitor PF543 (SphK inhibitor) ( Gonzalez-Fernandez et al., 2017)
SKI-II (SphK inhibitor, non-selective) ( Yang et al., 2013)
N,N-dimethylsphingosine (DMS, SphK inhibitor) ( Brunati et al., 2008; Wang et al., 2017b; Xiu et al., 2015)
S1P receptor agonist/antagonist FTY720 (S1PR1 and S1PR3 agonist) ( Brunati et al., 2008; King et al., 2017; Kong et al., 2014)
VPC23019 (S1PR1 and S1PR3 antagonist) ( Brunati et al., 2008; Yang et al., 2012; 2013)
SEW2871 (S1PR1 agonist) ( Ding et al., 2016)
W146 (S1PR1 antagonist) ( King et al., 2017; Liu et al., 2011; Yang et al., 2012; 2013)
JTE-013 (S1PR2 antagonist) ( Kageyama et al., 2012; Wang et al., 2017a; Xu et al., 2016; Yang et al., 2015)
Suramin (S1PR3 antagonist) ( Li et al., 2009a; 2009b)
KRP203 (FTY720 analog) ( Kaneko et al., 2006; Khattar et al., 2013)
CAY-10444 (S1PR3 antagonist) ( Yang et al., 2015)
VPC24191 (S1PR1 and S1PR3 antagonist) ( Al Fadel et al., 2016)
Other inhibitor Pertussis toxin (PTX; G-protein-coupled receptor signaling inhibitor) ( Brunati et al., 2008; Gonzalez-Fernandez et al., 2017; Yang et al., 2015)
Melatonin (melatonin receptors agonist)