Role for PPARγ in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts

Peroxisome proliferator-activated receptor (PPAR) gamma is a nuclear receptor central to glucose and lipid homeostasis. PPAR gamma role in nonalcoholic fatty liver disease is controversial because PPAR gamma overexpression is a general property of steatotic livers, but its activation by thiazolidinediones reduces hepatic steatosis. Here, we investigated hepatic PPAR gamma function by using Cre-loxP technology to generate hepatocyte (PPAR gamma(Delta hep))- and macrophage (PPAR gamma(Delta mac))-specific PPAR gamma-knockout mice. Targeted deletion of PPAR gamma in hepatocytes, and to a lesser extent in macrophages, protected mice against high-fat diet-induced hepatic steatosis. Down-regulated expression of genes involved in lipogenesis (SCD1, SREBP-1c, and ACC), lipid transport (CD36/FAT, L-FABP, and MTP), and beta-oxidation (PPAR alpha and ACO) was observed in PPAR gamma(Delta hep) mice. Moreover, PPAR gamma(Delta hep) mice showed improved glucose tolerance and reduced PEPCK expression without changes in Pcx, Fbp1, and G6Pc expression and CREB and JNK phosphorylation. In precision-cut liver slices (PCLSs) and hepatocytes, rosiglitazone either alone or in combination with oleic acid increased triglyceride accumulation, an effect that was blocked by the PPAR gamma antagonist biphenol A diglycidyl ether (BADGE). PCLSs and hepatocytes from PPAR gamma(Delta hep) mice showed blunted responses to rosiglitazone and oleic acid, whereas the response to these compounds remained intact in PCLSs from PPAR gamma(Delta mac) mice. Collectively, these findings establish PPAR gamma expression in hepatocytes as a prosteatotic factor in fatty liver disease.-Moran-Salvador, E., Lopez-Parra, M., Garcia-Alonso, V., Titos, E., Martinez-Clemente, M., Gonzalez-Periz, A., Lopez-Vicario, C., Barak, Y., Arroyo, V., Claria, J. Role for PPAR gamma in obesity-induced hepatic steatosis as determined by hepatocyte-and macrophage-specific conditional knockouts. FASEB J. 25, 2538-2550 (2011). www.fasebj.org