Sphingolipids in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma: Ceramide Turnover

Abstract

Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the main causes of chronic liver disease worldwide. NAFLD comprises a group of conditions characterized by the accumulation of hepatic lipids that can eventually lead to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), the fifth most common cancer type with a poor survival rate. In this context, several works have pointed out perturbations in lipid metabolism and, particularly, changes in bioactive sphingolipids, as a hallmark of NAFLD and derived HCC. In the present work, we have reviewed existing literature about sphingolipids and the development of NAFLD and NAFLD-derived HCC. During metabolic syndrome, considered a risk factor for steatosis development, an increase in ceramide and sphigosine-1-phosphate (S1P) have been reported. Likewise, other reports have highlighted that increased sphingomyelin and ceramide content is observed during steatosis and NASH. Ceramide also plays a role in liver fibrosis and cirrhosis, acting synergistically with S1P. Finally, during HCC, metabolic fluxes are redirected to reduce cellular ceramide levels whilst increasing S1P to support tumor growth.

Keywords: HCC; Metabolic syndrome; NAFLD; NASH; S1P; ceramide; cirrhosis; lipidomics; metabolomics; sphingolipids; sphingomyelin.

Figure 1

Liver disease progression: from steatosis to hepatocellular carcinoma. Schematic representation of the two-hit hypothesis and the progression of the disease, with characteristic H&E staining micrographs from each state of the pathology. A first hit leads an increased lipid accumulation in the liver, named steatosis. In a second hit reactive oxygen species (ROS), lipotoxicity, endoplasmic reticulum (ER) stress and mitochondrial dysfunction lead to non-alcoholic steatohepatitis (NASH) in 10%–30% patients. Sustained damage results in apoptosis, inflammation and extracellular matrix (ECM) deposition, leading to a fibrotic response and cirrhosis in 20% of patients. Finally, the 4%–27% of chronic patients can develop hepatocellular carcinoma (HCC).

Figure 2

Ceramide is the central molecule in sphingolipid metabolism and can be synthesized by three different pathways: de novo synthesis pathway, sphingomyelinase pathway and salvage pathway. (SPT = serine palmitoyltransferase; KDR = 3-keto-dihydrosphingosine reductase; CerS = ceramide synthase; CSase = ceramidase; Des = desaturase; SphK = sphingosine kinase; SPP = S1P phosphatase; SMase = sphingomyelinase; SMS = sphingomyelin synthase; CerK = ceramide kinase; C1PP = ceramide-1-phosphate phosphatase).