Weight loss amelioration of non-alcoholic steatohepatitis linked to shifts in hepatic ceramide expression and serum ceramide levels

Aim: Non-alcoholic steatohepatitis (NASH) is associated with increased hepatic insulin resistance. Ceramides and other toxic sphingolipids promote inflammation, lipotoxicity and insulin resistance; however, the role of ceramides in the pathogenesis of NASH has not been determined. This study characterizes expression of ceramide-related genes in human livers with NASH and examines the effects of weight loss on NASH and pro-ceramide gene expression in liver. Methods: Liver biopsies were obtained to assess the histopathological status of non-alcoholic fatty liver disease/NASH prior to and following completion of a 1-year course of implementing either lifestyle changes or a standard enrichment protocol designed to encourage weight loss. Liver biopsy samples were used to measure pro-ceramide gene expression by quantitative reverse transcriptase polymerase chain reaction analysis (qRT-PCR), and serum was used to measure ceramide immunoreactivity. Results: At baseline, serine palmitoyltransferase (SPTLC)2 (P = 0.02) and ceramide synthase (CER) 1 (P = 0.001) mRNA transcripts were less abundantly expressed in livers with NASH relative to normal controls. After weight loss (average 9.3%), SPTLC1 (P = 0.005) and uridine diphosphate glucose ceramide glucosyltransferase (UGCG) (P = 0.001) expression significantly declined while CER1 increased (P = 0.001) among subjects randomized to the lifestyle change subgroup. Reductions in calorie and fat consumption were significantly correlated with changes in ceramide-related gene expression. Finally, both net and relative reductions in serum ceramide levels were significantly greater in the lifestyles compared with the standard enrichment (control) protocol group (both P < 0.005). Conclusion: NASH is associated with increased insulin resistance and altered ceramide gene expression in liver. Weight loss-mediated reversal of NASH is associated with reduced pro-ceramide gene expression in liver.