BACKGROUND/AIMS: The molecular mechanisms leading to Non-Alcoholic Steatohepatitis (NASH) are not fully understood. In mice, NASH can be inhibited by fenofibrate, a synthetic agonist for the nuclear receptor peroxisome proliferator activated receptor alpha, which regulates hepatic triglyceride metabolism. This study aimed to elucidate the relation between steatosis and inflammation in NASH in a human-like hyperlipidemic mouse model. METHODS: Liver phenotype and gene expression were assessed in APOE2 knock-in mice that were fed a western-type high fat diet with or without co-administration of fenofibrate. RESULTS: In response to a western diet, APOE2 knock-in mice developed NASH characterized by steatosis and inflammation. Strikingly, macrophage accumulation in the liver preceded the steatosis during progression of the disease. This phenotype was in line with gene expression patterns, which showed regulation of two major groups of genes, i.e. inflammatory and lipid genes. Fenofibrate treatment decreased hepatic macrophage accumulation and abolished steatosis. Moreover, a marked reduction in the expression of inflammatory genes occurred immediately after fenofibrate treatment. CONCLUSIONS: These data indicate that inflammation might play an instrumental role during the development of NASH in this mouse model. Inhibition of NASH by fenofibrate may be due, at least in part, to its inhibitory effect on pro-inflammatory genes.
BACKGROUND/AIMS: The molecular mechanisms leading to Non-Alcoholic Steatohepatitis (NASH) are not fully understood. In mice, NASH can be inhibited by fenofibrate, a synthetic agonist for the nuclear receptor peroxisome proliferator activated receptor alpha, which regulates hepatic triglyceride metabolism. This study aimed to elucidate the relation between steatosis and inflammation in NASH in a human-like hyperlipidemic mouse model. METHODS: Liver phenotype and gene expression were assessed in APOE2 knock-in mice that were fed a western-type high fat diet with or without co-administration of fenofibrate. RESULTS: In response to a western diet, APOE2 knock-in mice developed NASH characterized by steatosis and inflammation. Strikingly, macrophage accumulation in the liver preceded the steatosis during progression of the disease. This phenotype was in line with gene expression patterns, which showed regulation of two major groups of genes, i.e. inflammatory and lipid genes. Fenofibrate treatment decreased hepatic macrophage accumulation and abolished steatosis. Moreover, a marked reduction in the expression of inflammatory genes occurred immediately after fenofibrate treatment. CONCLUSIONS: These data indicate that inflammation might play an instrumental role during the development of NASH in this mouse model. Inhibition of NASH by fenofibrate may be due, at least in part, to its inhibitory effect on pro-inflammatory genes.
Authors: Silvia Bijland; Elsbet J Pieterman; Annemarie C E Maas; José W A van der Hoorn; Marjan J van Erk; Jan B van Klinken; Louis M Havekes; Ko Willems van Dijk; Hans M G Princen; Patrick C N Rensen Journal: J Biol Chem Date: 2010-05-25 Impact factor: 5.157
Authors: Sally Yu Shi; Rubén García Martin; Robin E Duncan; Diana Choi; Shun-Yan Lu; Stephanie A Schroer; Erica P Cai; Cynthia T Luk; Kathryn E Hopperton; Anthony F Domenichiello; Christine Tang; Mark Naples; Mark J Dekker; Adria Giacca; Khosrow Adeli; Kay-Uwe Wagner; Richard P Bazinet; Minna Woo Journal: J Biol Chem Date: 2012-01-24 Impact factor: 5.157
Authors: Sergio Perez-Diaz; Lance A Johnson; Robert M DeKroon; Jose M Moreno-Navarrete; Oscar Alzate; Jose M Fernandez-Real; Nobuyo Maeda; Jose M Arbones-Mainar Journal: FASEB J Date: 2014-05-08 Impact factor: 5.191