Prevention of steatohepatitis by pioglitazone: Implication of adiponectin-dependent inhibition of SREBP-1c and inflammation

Background/Aims Peroxisome proliferator-activated receptor gamma (PPARγ) agonist drugs, like pioglitazone (PGZ), are proposed as treatments for steatohepatitis. Their mechanisms of action remain ill-clarified. Methods To test the hypothesis that PGZ improves steatohepatitis through adiponectin-depen...

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Bibliographic Details
Published in:Journal of hepatology 2009-03, Vol.50 (3), p.489-500
Main Authors: Da Silva Morais, Alain, Lebrun, Valérie, Abarca-Quinones, Jorge, Brichard, Sonia, Hue, Louis, Guigas, Bruno, Viollet, Benoit, Leclercq, Isabelle A
Format: Article
Language:English
Subjects:
Adiponectin - deficiency
Adiponectin - physiology
AMPK
Animals
Choline Deficiency - complications
DNA Primers
Fatty Liver - prevention & control
Female
Gastroenterology and Hepatology
Inflammation - prevention & control
Liver - enzymology
Liver - pathology
MCD diet
Methionine - deficiency
Mice
Mice, Inbred C57BL
Mice, Knockout
Mouse
PPARalpha
Protein Kinases - deficiency
Protein Kinases - genetics
Reverse Transcriptase Polymerase Chain Reaction
RNA - genetics
RNA - isolation & purification
SREBP-1c
Sterol Regulatory Element Binding Protein 1 - antagonists & inhibitors
Sterol Regulatory Element Binding Protein 1 - genetics
Thiazolidinediones - therapeutic use
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Summary:Background/Aims Peroxisome proliferator-activated receptor gamma (PPARγ) agonist drugs, like pioglitazone (PGZ), are proposed as treatments for steatohepatitis. Their mechanisms of action remain ill-clarified. Methods To test the hypothesis that PGZ improves steatohepatitis through adiponectin-dependent stimulation of AMPK and/or PPARα, mice lacking adiponectin (Adipo−/− ) or the AMPKα1 catalytic subunit (AMPKα1−/− ) or wild-type (Wt) mice were fed the methionine and choline deficient (MCD) diet, supplemented or not with PGZ. Results In Wt mice, PGZ increased circulating levels of adiponectin and reduced the severity of MCD-induced steatohepatitis but there was no evidence of activation of AMPK or PPARα and their downstream targets. By contrast, PGZ completely repressed nuclear translocation of SREBP-1c, a key transcription factor for de novo lipogenesis. This effect was lacking in Adipo−/− mice in which PGZ failed to prevent steatohepatitis. Surprisingly, AMPKα1−/− mice were resistant to MCD-induced steatohepatitis, a status also associated with repression of SREBP-1c. Conclusions The preventive effect of PGZ on MCD-induced steatohepatitis depends on adiponectin upregulation but apparently does not involve AMPK or PPARα activation. The inhibition of SREBP-1c and dependent repression of lipogenesis are likely to participate in this effect. The mechanisms by which PGZ and adiponectin control SREBP-1c and inflammation remain to be elucidated.
ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2008.10.027