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.

Remodeling Lipids in the Transition from Chronic Liver Disease to Hepatocellular Carcinoma

“…Ceramides and sphingomyelins are interconverted and are regulated by more than 28 enzymes that reflect the complexity of sphingolipids homeostasis [ 66 ]. Upregulation of serine palmitoyl transferase, a key enzyme of sphingolipids synthesis, has been linked to HCV replication and hepatic fibrosis process [ 67 , 68 ]. This report is in accordance with our finding of increased sphingolipids in blood of CLD patients compared to healthy control subjects.…”

Tri-Herbal Medicine Divya Sarva-Kalp-Kwath (Livogrit) Regulates Fatty Acid-Induced Steatosis in Human HepG2 Cells through Inhibition of Intracellular Triglycerides and Extracellular Glycerol Levels

“…The de novo ceramide synthesis that occurs using serine and palmitoyl CoA in the endoplasmic reticulum is upregulated in the presence of an excess of saturated fatty acids. Thus, an increase in ceramide levels has been known to promote triglyceride synthesis, induce hepatic lipid accumulation, lipotoxicity, and provoke apoptosis [ 39 , 40 ]. Intracellular increase in the triglyceride and extracellular lipid levels decrease in the glycerol level are the hallmarks of steatosis ailment [ 41 ].…”

Lipidomics Identified Lyso-phosphatidylcholine and Phosphatidylethanolamine as Novel Biomarkers for Diagnosis of Laryngeal Cancer

“…The imbalance in ceramide will greatly affect the physicochemical properties of cell, leading to cellular dysfunction. It has been demonstrated that ceramide metabolism is altered in numerous cancers characterized by an elevation of the Cer pro le in tumor tissue and cancer cells [7,12,13]. We speculated that the signi cant increase in the level of the Cer lipid class in LaC could have resulted from the elevated expression of the enzymes responsible for the synthesis of ceramide.…”

“…Lipidomics, focusing on comprehensive pro ling of lipids in complex biological matrice, is a powerful tool to identify disease-related lipid biomarkers, and to explore disordered lipid metabolism in the development of diseases. It has been widely applied in many studies, such as diabetes [4,5], lung cancer [6], liver cancer [7,8], and so on. Unfortunately, no laryngeal cancer-associate lipidomic study has yet been performed.…”