A novel agonist of PPAR-γ based on barbituric acid alleviates the development of non-alcoholic fatty liver disease by regulating adipocytokine expression and preventing insulin resistance

Non-alcoholic fatty liver disease (NAFLD) is a frequent kind of metabolic syndrome, which included a wide spectrum of liver damage and closely associated with insulin resistance and other metabolic syndromes such as obesity, type II diabetes, hyperglycemia, etc. Recently, a new series of PPAR gamma ligands based on barbituric acid has been designed, in which 5-(4-(benzyloxy)benzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (SKLB102) showed a high affinity with PPAR gamma. The current study aimed to evaluate the protective effect of SKLB102 on NAFLD and investigate the underlying mechanisms. In vivo, oral administration of SKLB102 prevented the pathological development, as demonstrated by reducing liver weight and visceral fat effectively, decreasing the serum levels of alanine transaminase,TNF-alpha and glucose, diminishing the hepatic triglyceride and malondialdehyde content and recovering the abnormal down-regulation of LDL Histological examination of liver sections by Oil Red 0 and H&E staining confirmed the protective effect of SKLB102 on NAFLD. Furthermore, SKLB102 elevated the serum level of adiponectin, reduced the serum level of leptin and prevented insulin resistance. Western blots indicated that SKLB102 increased the hepatic AMPK activities and CPT-1 expression. In vitro, SKLB102 showed the ability of significantly enhancing adiponectin expression and inhibiting leptin expression in 3T3-L1 adipocytes. Furthermore, SKLB102 could promote glucose consumption in HepG2 cells in the presence of 0.1 mu M insulin. In conclusion, our current study provided strong evidence that SKLB102 had potent ability to reduce fat deposition and protect liver against NAFLD through regulating adipocytokine expression and preventing insulin resistance, which might be of protective value for the prevention of NAFLD. (C) 2011 Elsevier B.V. All rights reserved.