Critical Roles of the Sphingolipid Metabolic Pathway in Liver Regeneration, Hepatocellular Carcinoma Progression and Therapy

Abstract

The sphingolipid metabolic pathway, an important signaling pathway, plays a crucial role in various physiological processes including cell proliferation, survival, apoptosis, and immune regulation. The liver has the unique ability to regenerate using bioactive lipid mediators involving multiple sphingolipids, including ceramide and sphingosine 1-phosphate (S1P). Dysregulation of the balance between sphingomyelin, ceramide, and S1P has been implicated in the regulation of liver regeneration and diseases, including liver fibrosis and hepatocellular carcinoma (HCC). Understanding and modulating this balance may have therapeutic implications for tumor proliferation, progression, and metastasis in HCC. For cancer therapy, several inhibitors and activators of sphingolipid signaling, including ABC294640, SKI-II, and FTY720, have been discussed. Here, we elucidate the critical roles of the sphingolipid pathway in the regulation of liver regeneration, fibrosis, and HCC. Regulation of sphingolipids and their corresponding enzymes may considerably influence new insights into therapies for various liver disorders and diseases.

Keywords: HCC; liver fibrosis; liver regeneration; the sphingolipid metabolic pathway.

Figure 1

Sphingolipid metabolic pathway in liver regeneration and HCC progression. Numerous agonists, including cytokines and growth factors, activate cytosolic SK to translocate to the plasma membrane and produce S1P. S1P can be irreversibly degraded by S1P lyase (SPL). It can also be dephosphorylated by S1P phosphatases (SPP). After being secreted by ABC transporters or Spns2, S1P binds and activates S1P receptors (S1PR1-5) and regulates numerous cellular functions such as proliferation, angiogenesis and migration. In de novo sphingolipid biosynthesis, serine and palmitoyl-CoA are converted to sphinganine and further modified to form ceramide. SM: sphingomyelin, Cer: ceramide, Cers: ceramide synthtase, ACdase: acid ceramidase, Sph: sphingosine, SK: sphingosine kinase, SPP: sphingosine phosphatase, SPL: sphingosine lyase, DES: dihydroceramide desaturase.

Figure 2

Immunological functions of sphingolipids. Increased intracellular and extracellular sphingolipids, such as S1P or ceramide, activate the immune response. The S1P/S1PR system plays a key role in neutrophil recruitment and monocyte activation. S1P also directly modulates functional activity of dendritic cells. Macrophage efferocytosis is a key player in the resolution of inflammation. DC: Dendritic cells, Treg: regulatory T cells.

Figure 3

S1PR signaling pathways in liver regeneration and HCC progression. Sphingosine-1-phosphate (S1P) acts as a lipid mediator of various cellular responses such as cell cycle, proliferation, and migration, and acts primarily through S1P receptors (S1PR1 to S1PR3). S1PR1 mediates cell migration via the Gi/Rac pathway, whereas S1PR2 mediates inhibition of migration via the G12/13/Rho pathway. SIPR3 also promotes cell migration via the Gi/Rac or Ras/ERK pathway. S1PR1 overexpression was positively correlated with vimentin and MMP-9 expression and negatively correlated with E-cadherin expression. In addition, S1PR1 overexpression induced EMT and enhanced tumor invasion and cancer stemness.

Figure 4

S1PR1 expression via EMT-induced vascular invasion and increased cancer stem cell properties in HCC metastasis and recurrence. S1PR1 overexpression, via EMT-induced vascular invasion and enhanced cancer stem cell properties, establishes a metastatic niche and increases the capacity for hematogenous metastasis as well as recurrence.