Increased serum concentration of ceramides in obese children with nonalcoholic fatty liver disease.

BACKGROUND: Hepatic lipid accumulation is closely related to the development of insulin resistance, which is regarded as one of the most significant risk factors of nonalcoholic fatty liver disease (NAFLD). Although the exact molecular pathway leading to impaired insulin signaling has not been definitively established, ceramides are suspected mediators of lipid induced hepatic insulin resistance. Therefore, the aim of the study was to evaluate the serum ceramides concentration in obese children with NAFLD.

METHODS: The prospective study included 80 obese children (aged 7-17 years, median 12 years) admitted to our Department to diagnose initially suspected liver disease. Patients with viral hepatitis (HCV, HBV, CMV), autoimmune (AIH), toxic and metabolic (Wilson's disease, alfa-1-antitrypsin deficiency) liver diseases and celiac disease were excluded. NAFLD was diagnosed based on pediatric diagnostic criteria in obese children with liver steatosis in ultrasound (US) as well as elevated alanine transaminase (ALT) serum activity after exclusion of other major liver diseases listed before. Ultrasonography was used as a screening method and for qualitative assessment of the steatosis degree (graded according to Saverymuttu scale). Advanced steatosis was defined as a score > 1. The total intrahepatic lipid content (TILC) was assessed by magnetic resonance proton spectroscopy (1 HMRS) which is the most accurate technique for assessment of ectopic fat accumulation. Fasting serum concentration of ceramides was measured in 62 children.

RESULTS: NAFLD was diagnosed in 31 children. Significant, positive correlation was found between total serum concentration of ceramides and insulin (r = 0.3, p = 0.02) and HOMA-IR (r = 0.28, p = 0.03). Total ceramide concentration as well as specific fatty acid-ceramides (FA-ceramides) concentrations, namely: myristic, palmitic, palmitoleic, stearic, oleic, behenic and lignoceric were significantly higher (p = 0.004, p = 0.003, p = 0.007, p < 0.001, p = 0.035, p = 0.008, p = 0.003, p = 0.006, respectively) in children with NAFLD compared to controls (n = 14). Moreover, children with NAFLD had significantly higher activity of ALT (p < 0.001) and GGT (p < 0.001), HOMA-IR (p = 0.04), BMI (p = 0.046), waist circumference (p = 0.01) steatosis grade in ultrasound (p < 0.001) and TILC in 1 HMRS (p < 0.001) compared to children without NAFLD. We did not find significant differences in total and FA-ceramide species concentrations between children with mild (grade 1) and advanced liver steatosis in ultrasonography (grade 2-3).

CONCLUSION: Elevated ceramide concentrations in obese patients together with their significant correlation with insulin resistance parameters suggest their association with molecular pathways involved in insulin signaling impairment known to be strongly linked to pathogenesis of non-alcoholic fatty liver disease.