Serum Ceramide Species Are Associated with Liver Cirrhosis and Viral Genotype in Patients with Hepatitis C Infection

Abstract

Hepatitis C virus (HCV) infection affects ceramide metabolism, and, here, we have evaluated associations of eight serum ceramide species with viral load, viral genotype, and disease markers in 178 patients with chronic HCV. In this cohort, ceramide d18:1;O2/16:0 was higher in the serum of the 20 diabetic patients compared to the patients without this complication. Moreover, ceramide d18:1;O2/24:0 was negatively correlated with age. Of note, all but ceramide d18:1;O2/16:0 and 26:0 were diminished in the serum of patients with liver cirrhosis and, with the exception of ceramide d18:1;O2/16:0, were negatively correlated with the model for end-stage liver disease (MELD) score. Most of the serum ceramides are carried in low-density lipoprotein (LDL), which rises following effective direct-acting antiviral (DAA) therapy. Ceramide d18:1;O2/24:0 recovered in parallel with LDL, whereas ceramide d18:1;O2/18:0 declined. Genotype-3-infected patients had the lowest ceramide levels, which were comparable to other genotypes after DAA treatment. Notably, ceramide d18:1;O2/23:0 and 24:0 were negatively correlated with the MELD score in patients with liver cirrhosis at the end of DAA therapy. Long-chain (LC) ceramides show adverse effects, whereas very-long-chain (VL) species have protective functions in the liver. The ratio of VL/LC ceramides was higher in non-cirrhosis patients than cirrhosis patients and further increased at the end of therapy in this subgroup. In summary, our study shows that serum ceramide levels are related to liver cirrhosis and viral genotype. Whether the more favorable serum ceramide profile in non-cirrhosis patients, before and after DAA therapy, is of pathophysiological importance needs further investigation.

Hepatitis C Virus Infection Upregulates Plasma Phosphosphingolipids and Endocannabinoids and Downregulates Lysophosphoinositols

“…This same group investigated eight serum ceramide concentrations in 178 patients with chronic HCV infection and noted that most ceramides are carried on LDL, which rises after effective DAA therapy. Again, they reported differences in cirrhotic versus noncirrhotic patients, especially in the ratio of long-chain ceramides (such as d18:1; O2/18:0) to very long-chain ceramides (such as d18:1; O2/24:0) [ 6 ]. In our untargeted lipidomic analysis here, we did not observe changes in these specific ceramide molecules but did observe 2.8- to 3.4-fold diminished plasma concentrations for two galactoceramides, one containing a long-chain ceramide (d18:1/16:0) and the other a very long-chain ceramide (d18:1/20:0).…”

“…For example, cholesterol and phosphatidylcholines accumulate in the endoplasmic reticulum during HCV infection [ 3 ], while fatty acid synthesis is attenuated, and β-oxidation increases in the liver cells [ 4 ]. Circulating HCV particles are physically associated with lipoproteins in infectious hybrid lipid aggregates known as lipoviral complexes, which bear a greater similarity to low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) particles than to a virion, with a composition of cholesterol, triglycerides, phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylcholines, and sphingolipids [ 5 , 6 ]. These hijacked complexes appear to conceal viral epitopes to escape immune surveillance and utilize lipoprotein receptors for attachment and entry into hepatocytes [ 5 ].…”

“…The diagnosis of the fatty liver occurs commonly in HCV-infected patients. It is believed that this may be due to the impaired secretion of VLDL, leading to reduced serum LDL [ 6 ]. Clearly, the metabolic pathways involving the aforementioned multiple classes of lipids that comprise lipoproteins may be affected in the liver.…”

HCV Infection and Liver Cirrhosis Are Associated with a Less-Favorable Serum Cholesteryl Ester Profile Which Improves through the Successful Treatment of HCV

“…Interestingly, the CE/FC ratio increased during DAA treatment in the cirrhosis and non-cirrhosis group, showing that the cholesterol esterification rate is higher in both cohorts. Liver function does not greatly improve during DAA therapy [ 7 , 8 ] and the MELD score of our patient group did not change [ 46 ], indicating that the cholesterol esterification rate is not solely affected by liver disease severity.…”

“…Individual laboratory values of ≥95% of the patients were available. Laboratory parameters of this study group have been published in an open access journal [ 46 ].…”