Variations in serum sphingolipid levels associate with liver fibrosis progression and poor treatment outcome in hepatitis C virus but not hepatitis B virus infection

Abstract

Ablation of very-long-chain ceramides (Cers) with consecutive elevations in sphinganine levels has been shown to cause a severe hepatopathy in a knockout mouse model. We have recently shown that serum sphingolipids (SLs) are deregulated in patients with chronic liver disease. However, their role as possible biomarkers in liver fibrosis remains to date unexplored. We assessed, using liquid chromatography/tandem mass spectrometry, serum concentrations of various SL metabolites in 406 patients with chronic viral hepatitis, 203 infected with genotype 1 hepatitis C virus (HCV) and 203 with hepatitis B virus (HBV), respectively. We observed significant variations of serum SLs, with sphingosine and sphinganine being, both in univariate (P < 0.05) as well as in multivariate analysis, significantly associated to severity of liver fibrosis in HCV-infected patients (odds ratio [OR]: 1.111; confidence interval [CI]: 1.028-1.202; P 5 0.007 and OR, 0.634; CI, 0.435-0.925; P 5 0.018, respectively). Serum SLs correlated significantly with serum triglyceride and cholesterol levels as well as with insulin resistance, defined by the homeostatic model assessment index, in HCV patients. Sustained viral response rates in HCV patients were independently predicted by serum C24Cer (OR, 0.998; CI, 0.997-0.999; P 5 0.001), its unsaturated derivative C24:1Cer (OR, 1.001; CI, 1.000-1.002; P 5 0.059), and C18:1Cer (OR, 0.973; CI, 0.947-0.999; P 5 0.048), together with ferritin (OR, 1.006; CI, 1.003-1.010; P < 0.001), alkaline phosphatase (OR, 1.020; CI, 1.001-1.039; P 5 0.032), and interleukin-28B genotype (OR, 9.483; CI,; P < 0.001). Conclusion: Our study demonstrates a tight interaction between variations in serum SL levels and progression of liver fibrosis as well as responsiveness to antiviral therapy. Particularly, sphingosine, sphinganine, and C24Cer appear as promising novel biomarkers in chronic HCV infection and should be further evaluated within the noninvasive prediction of liver fibrosis. (HEPATOLOGY 2015;61:812-822)

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

“…Disruptions of SL metabolism were described in hepatitis B (HBV) and C (HCV) infection, including increased expression of genes that is involved in the metabolism and transport of SLs, phospholipids, and fatty acids (33, 35, 45-47, 165, 169, 180, 184). C18DHC, C24Cer, SPH, and sphinganine were significantly linked with the level of liver fibrosis (62,44,66). However, a high correlation between variations in serum SL levels and responsiveness to antiviral therapy was shown.…”

“…Analysis of lipids from the hepatic portal system at the time of surgery revealed that PG and PE classes were increased in NASH subjects; moreover, few alterations were noted in adipose tissue lipid efflux (9,10,39). Serum SLs are dysregulated in patients with several chronic liver diseases, suggesting their role in liver damage (44,62,66). Disruptions of SL metabolism were described in hepatitis B (HBV) and C (HCV) infection, including increased expression of genes that is involved in the metabolism and transport of SLs, phospholipids, and fatty acids (33, 35, 45-47, 165, 169, 180, 184).…”

“…Both HCV and NAFLD induce upregulation of serum ASMase, which appears as a biomarker for these disorders (48,63,67). Serum SLs is correlated with the degree of severity in insulin resistance alongside with serum triglyceride and cholesterol levels (44,62,66). Cer affects hepatocellular susceptibility to various stimuli, regulation of viral replication, and trafficking (6, 7, 49 -51, 108, 112, 175, 179).…”

“…Methionine is primarily metabolized in the liver, and its clearance is delayed in cirrhosis (61, 140,144). Disrupted methionine metabolism, exemplified by decreased S-adenosyl-L-methionine (SAM) and/or increased S-adenosylhomocysteine (SAH) and homocysteine (Hcy) levels, and PC depletion were described in steatohepatitis (62,112,116). SAM is essential in liver physiology, because of its functions as a methyl donor and glutathione (GSH) precursor.…”

“…Increased levels of GM3 in rafts impair insulin signaling, resulting in insulin resistance. The ganglioside GM3 is a negative regulator of insulin sensitivity (58, 62,128). In animal models of GD, lipid composition is altered, contributing to impaired insulin signaling (49, 52, 120), whereas, in fibroblasts from GD patients, decreased degradation and increased anabolism of GC were detected.…”