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-dependent stimulation of AMPK and/or PPARα, mice lacking adiponectin (Adipo^-/-) or the AMPKα1 catalytic subunit (AMPKα1^-/-) or wildtype (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, PGZcompletely repressed nuclear translocation of SREBP-1c, a key transcription factor for de novo lipogenesis. This effectwas 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 pregulation 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.