Caffeine Suppresses the Activation of Hepatic Stellate Cells cAMP-Independently by Antagonizing Adenosine Receptors

Abstract

During liver injury, hepatic stellate cells (HSCs) are activated by various cytokines and transdifferentiated into myofibroblast-like activated HSCs, which produce collagen, a major source of liver fibrosis. Therefore, the suppression of HSC activation is regarded as a therapeutic target for liver fibrosis. Several epidemiological reports have revealed that caffeine intake decreases the risk of liver disease. In this study, therefore, we investigated the effect of caffeine on the activation of primary HSCs isolated from mice. Caffeine suppressed the activation of HSC in a concentration-dependent manner. BAPTA-AM, an intracellular Ca 2 chelator, had no effect on the caffeine-induced suppression of HSC activation. None of the isoformselective inhibitors of phosphodiesterase1 to 5 affected changes in the morphology of HSC during activation, whereas CGS-15943, an adenosine receptor antagonist, inhibited them. Caffeine had no effect on intracellular cAMP level or on the phosphorylation of extracellular signal-regulated kinase (ERK)1/2. In contrast, caffeine significantly decreased the phosphorylation of Akt1. These results suggest that caffeine inhibits HSC activation by antagonizing adenosine receptors, leading to Akt1 signaling activation.

Purinergic signaling in hepatic disease

“…The role for ADO in HSC phenotype transformation is controversial. Some evidence supports the fact that ADO, acting through A2AR, induces HSC activation [62,[67][68][69]. In primary cultures of rat HSCs, the nucleoside was able to induce a concomitant increase of procollagen I and III transcripts and their respective proteins.…”

Extracellular adenosine: a critical signal in liver fibrosis

“…Third, the transduction mechanisms i.e., coupling systems and/or effectors linked to the activation of adenosine receptors are not fully characterized in liver myofibroblast subpopulations. Recently, it was reported that caffeine-mediated A 2A receptor antagonism could prevent the activation of primary isolated mouse HSC, in Akt-dependent manner (78). Surprisingly, the observed effect did not apparently involve changes in intracellular cAMP and Ca 2ϩ levels.…”

Interaction between the patatin‐like phospholipase domain‐containing protein 3 genotype and coffee drinking and the risk for acute alcoholic hepatitis

“…(21) Lastly, caffeine's protective mechanism may be mediated through its antagonistic effect on adenosine receptors and thus inhibition of collagen synthesis by hepatic stellate cells. (23) While caffeine might be the mechanistically important component of coffee, some studies have suggested that the protective effect of coffee against hepatic injury may be secondary to noncaffeine-mediated mechanisms, (13,24) as demonstrated by the protective effects of decaffeinated coffee. However, the evidence is weaker overall for decaffeinated than for regular coffee.…”