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Role for PPARγ in obesity‐induced hepatic steatosis as determined by hepatocyte‐ and macrophage‐specific conditional knockouts
Author(s) -
MoránSalvador Eva,
LópezParra Marta,
GarcíaAlonso Verónica,
Titos Esther,
MartínezClemente Marcos,
GonzálezPériz Ana,
LópezVicario Cristina,
Barak Yaacov,
Arroyo Vicente,
Clària Joan
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-173716
Subject(s) - steatosis , rosiglitazone , cd36 , endocrinology , medicine , peroxisome proliferator activated receptor , fatty liver , hepatocyte , lipogenesis , nonalcoholic fatty liver disease , chemistry , nuclear receptor , lipid metabolism , biology , receptor , biochemistry , transcription factor , disease , gene , in vitro
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 over‐expression is a general property of steatotic livers, but its activation by thiazolidinediones reduces hepatic steatosis. Here, we investigated hepatic PPARγ function by using Cre‐ lox P 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.—Morán‐Salvador, E., López‐Parra, M., García‐Alonso, V., Titos, E., Martínez‐Clemente, M., González‐Périz, A., López‐Vicario, C., Barak, Y., Arroyo, V., Clària, J. Role for PPARγ in obesity‐induced hepatic steatosis as determined by hepatocyte‐ and macrophage‐specific conditional knockouts. FASEB J. 25, 2538–2550 (2011). www.fasebj.org