Down-regulation of SREBP-1c is associated with the development of burned-out NASH

Background & Aims: It is well-known that hepatic triglycerides (TG) diminish with the progression of non-alcoholic steatohepatitis (NASH), which has been designated as burned-out NASH, but its mechanism remains unclear. We aimed to explore the changes in hepatic fatty acid (FA) and TG metabolism with disease progression. Methods: Hepatic expression of key genes in healthy individuals (n = 6) and patients with simple steatosis (SS, n = 10), mild NASH (fibrosis stage 1-2, n = 20), and advanced NASH (fibrosis stage 34, n = 20) were assessed by quantitative polymerase chain reaction. Results: Hepatic expression of genes related to FA uptake and oxidation and very-low-density lipoprotein synthesis/export did not differ among the groups. However, the mRNA levels of sterol-regulatory element-binding protein (SREBP)-1c and its downstream genes FA synthase, acetyl-coenzyme A carboxylase 1, and diacylglycerol acyltransferase 1 were inversely correlated with fibrosis stage. Immunoblot analysis revealed a remarkable reduction in mature SREBP-1c levels in advanced NASH. Furthermore, hepatic expression of tumor necrosis factor-a increased in accordance with fibrosis progression, which was possibly related to the decrease in hepatic SREBP-1c expression. Conclusions: Down-regulation of SREBP-1c and lipogenic enzymes may be associated with the development of burned-out NASH. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.