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. 2009 Jun;97(2):114-20.
doi: 10.1016/j.ymgme.2009.02.005. Epub 2009 Feb 26.

Calpain activation is required for homocysteine-mediated hepatic degradation of inhibitor I kappa B alpha

Julien Hamelet  1 , Jean-Pierre Couty, Anne-Marie Crain, Christophe Noll, Catherine Postic, Jean-Louis Paul, Jean-Maurice Delabar, Mireille Viguier, Nathalie Janel
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Calpain activation is required for homocysteine-mediated hepatic degradation of inhibitor I kappa B alpha

Julien Hamelet et al. Mol Genet Metab. 2009 Jun.

Abstract

Hepatic steatosis is a clinical feature observed in severe hyperhomocysteinemic patients. In mice, cystathionine beta synthase (CBS) deficiency, the most common cause of severe hyperhomocysteinemia, is also associated with steatosis, fibrosis and inflammation. Proinflammatory cytokines usually induce apoptosis. However, hyperhomocysteinemia does not increase apoptosis in liver of CBS-deficient mice compared to wild type mice. The aim of the study was to analyze the activation state of the NF-kappaB pathway in liver of CBS-deficient mice and to investigate its possible involvement in anti-apoptotic signals. We analyzed the level of I kappaB alpha in liver of CBS-deficient mice. A co-culture of primary hepatocytes and Kupffer cells was also used in order to investigate how I kappaB alpha degradation occurs in response to homocysteine. We found lower I kappaB alpha level not only in liver of CBS-deficient mice but also in hepatocyte/Kupffer cell co-culture. The homocysteine-mediated I kappaB alpha enhanced proteolysis occurred via calcium-dependent calpains, which was supported by an increased level of calpain activity and a reduced expression of calpastatin in liver of CBS-deficient mice. Intraperitoneal administration of the inhibitor PDTC normalized the expression of two genes induced by NF-kappaB activation, heme oxygenase-1 and cellular inhibitor of apoptosis 2. Moreover, PDTC administration induced an increase of caspase-3 activity in liver of CBS-deficient mice. Our results suggest that hyperhomocysteinemia induces calpain-mediated I kappaB alpha degradation which is responsible for anti-apoptotic signals in liver.

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