Abstract
Hepatic stellate cell (HSC) activation is an essential event during alcoholic liver fibrosis. Evidence suggests that adenosine aggravates liver fibrosis via the adenosine A2A receptor (A2AR). Caffeine, which is being widely consumed during daily life, inhibits the action of adenosine. In this study, we attempted to validate the hypothesis that caffeine influences acetaldehyde-induced HSC activation by acting on A2AR. Acetaldehyde at 50, 100, 200, and 400 μM significantly increased HSC-T6 cells proliferation, and cell proliferation reached a maximum at 48 h after exposure to 200 μM acetaldehyde. Caffeine and the A2AR antagonist ZM241385 decreased the cell viability and inhibited the expression of procollagen type I and type III in acetaldehyde-induced HSC-T6 cells. In addition, the inhibitory effect of caffeine on the expression of procollagen type I was regulated by A2AR-mediated signal pathway involving cAMP, PKA, SRC, and ERK1/2. Interestingly, caffeine’s inhibitory effect on the expression of procollagen type III may depend upon the A2AR-mediated P38 MAPK-dependent pathway. Conclusions: Caffeine significantly inhibited acetaldehyde-induced HSC-T6 cells activation by distinct A2AR mediated signal pathway via inhibition of cAMP-PKA-SRC-ERK1/2 for procollagen type I and via P38 MAPK for procollagen type III.
Highlights
Alcoholic liver disease (ALD) encompasses a spectrum of hepatic injuries caused by long-term heavy drinking, and it is a major cause of chronic liver disease worldwide [1,2]
To mimic the model of alcohol-induced liver fibrosis, Hepatic stellate cell (HSC)-T6 cells were treated with different concentrations of acetaldehyde
A key event in the pathogenesis of hepatic fibrosis is the transition of quiescent HSCs into activated myofibroblasts, with an increase in the expression of collagen production, which results in hepatic fibrosis [29]
Summary
Alcoholic liver disease (ALD) encompasses a spectrum of hepatic injuries caused by long-term heavy drinking, and it is a major cause of chronic liver disease worldwide [1,2]. ALD has become a serious global health problem because of the striking increase in alcohol consumption [3]. Pathologic stages of ALD comprise of steatosis (alcoholic fatty liver), steato-hepatitis (alcoholic hepatitis) and liver fibrosis/cirrhosis. Steatosis and steatohepatitis represent the early stage of ALD and as precursor lesion of fibrosis/cirrhosis [4,5]. Alcoholic liver fibrosis is regarded as a turning point in ALD [6]. The study of the pathogenesis and therapeutic targets of alcoholic liver fibrosis has received increasing attention
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