Role for PPARγ in obesity‐induced hepatic steatosis as determined by hepatocyte‐ and macrophage‐specific conditional knockouts
| Autor: | Ana González-Périz, Marcos Martínez-Clemente, Verónica García-Alonso, Eva Morán-Salvador, Joan Clària, Vicente Arroyo, Esther Titos, Marta López-Parra, Cristina López-Vicario, Yaacov Barak |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
Kupffer Cells CD36 Gene Expression Peroxisome proliferator-activated receptor Biology Biochemistry Mice Non-alcoholic Fatty Liver Disease Internal medicine Nonalcoholic fatty liver disease Genetics medicine Animals Obesity Molecular Biology DNA Primers Mice Knockout chemistry.chemical_classification Base Sequence Fatty liver medicine.disease Dietary Fats Fatty Liver PPAR gamma Glucose medicine.anatomical_structure Endocrinology chemistry Organ Specificity Hepatocyte Gene Targeting Lipogenesis Hepatocytes biology.protein Steatosis Rosiglitazone Biotechnology medicine.drug |
| Zdroj: | The FASEB Journal. 25:2538-2550 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.10-173716 |
| Popis: | Peroxisome proliferator-activated receptor (PPAR) γ is a nuclear receptor central to glucose and lipid homeostasis. PPARγ role in nonalcoholic fatty liver disease is controversial because PPARγ overexpression is a general property of steatotic livers, but its activation by thiazolidinediones reduces hepatic steatosis. Here, we investigated hepatic PPARγ function by using Cre-loxP technology to generate hepatocyte (PPARγ(Δhep))- and macrophage (PPARγ(Δmac))-specific PPARγ-knockout mice. Targeted deletion of PPARγ 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 β-oxidation (PPARα and ACO) was observed in PPARγ(Δhep) mice. Moreover, PPARγ(Δhep) 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 PPARγ antagonist biphenol A diglycidyl ether (BADGE). PCLSs and hepatocytes from PPARγ(Δhep) mice showed blunted responses to rosiglitazone and oleic acid, whereas the response to these compounds remained intact in PCLSs from PPARγ(Δmac) mice. Collectively, these findings establish PPARγ expression in hepatocytes as a prosteatotic factor in fatty liver disease. |
| Databáze: | OpenAIRE |
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