Prevention of steatohepatitis by pioglitazone: implication of adiponectin-dependent inhibition of SREBP-1c and inflammation.
OBJECTIVE
Peroxisome proliferator-activated receptor gamma (PPARgamma) 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 PPARalpha, mice lacking adiponectin (Adipo(-/-)) or the AMPKalpha1 catalytic subunit (AMPKalpha1(-/-)) 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 PPARalpha 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, AMPKalpha1(-/-) 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 PPARalpha 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.
Da Silva Morais
Alain
A
Laboratoire de Gastro-entérologie, Université Catholique de Louvain, GAEN 53/79, Brussels, Belgium.
Lebrun
Valérie
V
Abarca-Quinones
Jorge
J
Brichard
Sonia
S
Hue
Louis
L
Guigas
Bruno
B
Viollet
Benoit
B
Leclercq
Isabelle A
IA
D000091162:AMP-Activated Protein Kinase Kinases; D052242:Adiponectin / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D002796:Choline Deficiency / Q000150:complications; D017931:DNA Primers; D005234:Fatty Liver / Q000517:prevention & control*; D005260:Female; D007249:Inflammation / Q000517:prevention & control*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077205:Pioglitazone; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D045162:Thiazolidinediones / Q000627:therapeutic use*
D052242:Adiponectin; D017931:DNA Primers; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones; D012313:RNA; D008715:Methionine; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D000077205:Pioglitazone