Akt1 is a key molecule for caffeine-induced inhibition of hepatic stellate cell activation

[Speaker] Momoka Yamaguchi:1
[Co-author] Tomoya Morishita:1, Shin-Ya Saito:1, Tomohisa Ishikawa:1
1:Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Japan

 Hepatic stellate cells (HSCs), one of liver nonparenchymal cells, exist in the space of Disse, a gap of hepatocytes and sinusoidal endothelial cells. Under physiological conditions, HSCs store oil droplets containing vitamin A and play a role in the regulation of vitamin A homeostasis. These are called quiescent HSCs. During liver injury, HSCs are activated by various cytokines and transdifferentiated into myofibroblast-like activated HSCs. As compared with quiescent HSCs, activated HSCs are large, secret cytokines, and show increases in proliferation potency, alpha-smooth muscle actin expression, and collagen production, leading to liver fibrosis. HSCs are activated also by paracrine signaling from various neighboring cells, such as Kupffer cells, sinusoidal endothelial cells, hepatocytes, and platelets. Furthermore, the activation of HSCs is enhanced by autocrine signaling. Thus, HSCs seem to play a critical role in the progression from liver fibrosis to hepatic cirrhosis and hepatoma. Unfortunately, there is no effective therapy for liver fibrosis yet. Since quiescent HSCs produce matrix metalloproteinase which degrades collagen, the suppression of HSC activation or the reversion of activated HSC to quiescent HSC is expected to be a therapeutic target for liver fibrosis.
 Caffeine is widely ingested in coffee, green tea, black tea, and chocolate. Several epidemiologic studies have suggested that intake of coffee and green tea decreases the risk of liver disease. In the present study, therefore, we investigated the underlying mechanism of the inhibition by caffeine of HSC activation induced by fetal bovine serum in primary HSCs isolated from mice.
 Caffeine suppressed the activation of HSCs in a concentration-dependent manner. BAPTA-AM, an intracellular Ca2+ chelator, had no effect on the caffeine-induced suppression of HSC activation. None of the isoform-selective inhibitors of phosphodiesterase 1 to 5 affected changes in the morphology of HSCs during activation, whereas CGS-15943, an adenosine receptor antagonist, inhibited them. Caffeine had no effect on intracellular cAMP levels or the phosphorylation of ERK1/2. In contrast, caffeine significantly decreased the phosphorylation of Akt1. These results suggest that caffeine inhibits HSC activation by antagonizing adenosine receptors that stimulate the Akt1 pathway.

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