Upregulation of Kupffer cell α2A-Adrenoceptors and downregulation of MKP-1 mediate hepatic injury in chronic alcohol exposure

Abstract

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-α, 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 α2A-adrenoceptors (α2A-AR) to cause TNF-α 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-α in the liver. There was a 75% and 62% decrease in MKP-1 mRNA and protein levels in the liver, respectively. In-vitro experiments revealed 121% and 98% increase in TNF-α and α2A-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 α2A-AR to release TNF-α. Alcohol induced downregulation of MKP-1 leads to further release of TNF-α and hepatic injury.

Carvedilol improves ethanol‐induced liver injury via modifying the interaction between oxidative stress and sympathetic hyperactivity in rats

“…Studies have reported that chronic alcohol consumption induced liver injury associated with sympathetic hyperactivity, and implicated ROS in the pathogenesis of activation of the SNS, which may affect liver injury by modulating cellular oxidative damage . The major source of ROS is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an enzyme that can be activated during ethanol metabolism, leading to the production of superoxide anions (O – 2 ) in the liver.…”

“…1 In the present study, 49-day ethanol consumption induced the oxidant-antioxidant balance shift toward oxidative damage predominance as evidenced by the increase in the production of 8-OHdG and the decrease in the cellular content of SOD-1 (Figs 3,4). Studies have reported that chronic alcohol consumption induced liver injury associated with sympathetic hyperactivity, 9,10,33 and implicated ROS in the pathogenesis of activation of the SNS, which may affect liver injury by modulating cellular oxidative damage. [34][35][36] The major source of ROS is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an enzyme that can be activated during ethanol metabolism, leading to the production of superoxide anions (O -2) in the liver.…”

Suppression of Dual Specificity Phosphatase I Expression Inhibits Hepatitis C Virus Replication

“…However, little is known about the role of DUSP1 in the liver [ 16 , 17 ]; in particular, the association of DUSP1 with HCV infection remains unclear. Also, the relationships between IFN and DUSP1-associated signaling have not been elucidated.…”

Prefrontal Limbic-Striatal Circuits and Alcohol Addiction in Humans

“…Previous research indicates a chronic alcohol-induced, upregulated HPA axis system including corticotropinreleasing hormone (CRH) and noradrenergic signaling (Ajakaiye et al, 2011;Koob et al, 2004;Richardson, Lee, O'Dell, Koob, & Rivier, 2008;Sinha et al, 2009) in PLScircuit regions such as the amygdala with changes in related projections to the prefrontal cortex (Koob, 2009;Koob et al, 2004). Upregulation of these central stress pathways parallels changes in peripheral stress pathways as documented by higher basal adrenocorticotrophin (ACTH) and cortisol, blunted stress-induced ACTH and cortisol responses, and higher basal heart rate and lower heart rate variability in alcohol dependence (Adinoff, Iranmanesh, Veldhuis, & Fisher, 1998;Ingjaldsson, Laberg, & Thayer, 2003;Richardson et al, 2008;Shively et al, 2007;Sinha et al, 2009;Thayer, Hall, Sollers, & Fischer, 2006).…”