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.