Prevention of steatohepatitis by pioglitazone: Implication of adiponectin-dependent inhibition of SREBP-1c and inflammation.
(2009) Journal of Hepatology — Vol. 50, n° 3, p. 489-500 (2009)
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- BACKGROUND/AIMS: 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.
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Da Silva Morais, A., Lebrun, V., Abarca-Quinones, J., Brichard, S., Hue, L., Guigas, B., Viollet, B., & Leclercq, I. (2009). Prevention of steatohepatitis by pioglitazone: Implication of adiponectin-dependent inhibition of SREBP-1c and inflammation. Journal of Hepatology, 50(3), 489-500. https://doi.org/10.1016/j.jhep.2008.10.027 (Original work published 2009)