Upregulation of Kupffer cell alpha(2A)-Adrenoceptors and downregulation of MKP-1 mediate hepatic injury in chronic alcohol exposure

作者：Ajakaiye Michael A; Jacob Asha; Wu Rongqian; Zhou Mian; Ji Youxin; Dong Weifeng; Wang Zhimin; Qiang Xiaoling; Chaung Wayne W; Nicastro Jeffrey; Coppa Gene F; Wang Ping^*

来源：Biochemical and Biophysical Research Communications, 2011, 409(3): 406-411.

DOI：10.1016/j.bbrc.2011.05.007

• Chronic alcohol
• alpha(2A)-Adrenoceptor
• MKP-1
• Liver injury

Alcohol-induced liver disease is associated with unacceptable morbidity and mortality. When activated, Kupffer cells (KCs), the resident macrophages in the liver, release proinflammatory cytokine TNF-alpha, a key mediator of hepatic damage. Although chronic alcohol causes increase in norepinephrine (NE) release leading to hepatic dysfunction, the mechanism of NE-induced hepatic injury in chronic alcohol exposure has not been elucidated. This study was conducted to determine whether chronic alcohol exposure increases NE and upregulates KC alpha(2A)-adrenoceptors (alpha(2A)-AR) to cause TNF-alpha release. We also examined the role of mitogen activated protein kinase (MAPK) phosphatase-1 (MKP-1) in this process. Male adult rats were fed the Lieber-DeCarli liquid diet containing alcohol as 36% of total calories. The animals were sacrificed after 6 weeks and blood and liver samples were harvested for further analysis. KCs from healthy male rats were cultured with alcohol for 7 days, and cells then harvested for RNA and protein analyses. Chronic alcohol exposure resulted in hepatic damage. Alcohol caused a 276% increase in circulating NE and 86% increase in TNF-alpha in the liver. There was a 75% and 62% decrease in MKP-1 mRNA and protein levels, respectively in the liver. In-vitro experiments revealed 121% and 98% increase in TNF-alpha and alpha(2A)-AR mRNA levels with alcohol exposure, respectively, and a 32% decrease in MKP-1 mRNA compared to controls. In summary, chronic alcohol exposure elevates NE and upregulates KC alpha(2A)-AR to release TNF-alpha. Alcohol induced downregulation of MKP-1 leads to further release of TNF-alpha and hepatic injury.

• 出版日期2011-6-10
• 单位河北医科大学