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

Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY 11030, United States.
Biochemical and Biophysical Research Communications (Impact Factor: 2.28). 06/2011; 409(3):406-11. DOI: 10.1016/j.bbrc.2011.05.007
Source: PubMed

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 α(2A)-adrenoceptors (α(2A)-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, respectively in the liver. In-vitro experiments revealed 121% and 98% increase in TNF-α and α(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 α(2A)-AR to release TNF-α. Alcohol induced downregulation of MKP-1 leads to further release of TNF-α and hepatic injury.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Our previous studies have shown that dioscin has protective effect against liver injury. However, the action of the compound against ethanol-induced liver injury is still unknown. In the present paper, ethanol-induced acute and chronic liver damage rat models were used, and the results showed that dioscin significantly alleviated liver steatosis, reduced the levels of alanine aminotransferase, aspartate aminotransferase, total triglyceride (TG), total cholesterol and malondialdehyde, and increased the levels of high-density lipoprotein, superoxide dismutase, glutathione and glutathione peroxidase. Transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays showed that dioscin prevented mitochondrial ultrastructural alterations and apoptosis caused by ethanol. In addition, dioscin significantly inhibited ethanol-induced cytochrome P450 2E1 activation, down-regulated the levels of mitogen-activated protein kinases phosphorylation, inhibited the expressions of nuclear factor kappa B, glucose regulated protein 78, activating transcription factor 6 and alpha subunit of translation initiation factor 2 to attenuate oxidative damage, decreased the expressions of tumor necrosis factor alpha and interleukin-6, and down-regulated the expressions of apoptosis-related proteins including p53, caspase-3, caspase-9, poly (ADP-ribose)-polymerase and cytokeratin-18. Further investigation indicated that dioscin markedly increased the expressions of peroxisome proliferators-activated receptor α and its target genes including medium-chain acyl-CoA dehydrogenase, carnitine palmitoyl-CoA transferase I and acyl-CoA oxidase to advance fatty acid β-oxidation, up-regulated the expressions of acyl-CoA synthetase long-chain family member 1, acyl-CoA synthetase long-chain family member 5, alpha-aminoadipic semialdehyde dehydrogenase and acyl-CoA dehydrogenase to promote fatty acid metabolism, and down-regulated the expressions of glycerol-3-phosphate acyltransferase, diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 to accelerate TG synthesis. However, dioscin had no effects on the expressions of sterol regulatory element-binding protein-1c, fatty acid synthase, acetyl-CoA carboxylase 1 and stearoyl-CoA desaturase 1 associated with fatty acid synthesis. In conclusion, dioscin shows excellent protective effect against ethanol-induced liver injury through ameliorating ethanol-induced oxidative stress, mitochondrial function, inflammatory cytokine production, apoptosis and liver steatosis, which should be developed as a new drug for the treatment of ethanol-induced liver injury in the future.
    Archives of Toxicology 10/2013; · 5.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: AIM: Oxidative stress is major pathway mediating ethanol hepatotoxicity and liver injury. We previously found that carvedilol, which can block the sympathetic nervous system via β1, β2 and α1 adrenoreceptors, modifies ethanol-induced production of lipogenesis- and fibrogenesis-related mediators from hepatic stellate cells (HSCs). In the present study, we assessed the effects of carvedilol on ethanol-induced liver injury, hepatic insulin resistance, and the interaction between oxidative stress and sympathetic hyperactivity in rats with alcoholic fatty liver disease (AFLD). METHODS: Male Wistar rats were pair-fed for 49 days and divided into 4 groups: control and ethanol liquid-diet-fed rats with and without 7-day carvedilol treatment. Rats' sympathetic activity, hepatic oxidative stress, hepatic insulin resistance, and liver injury were evaluated based on biochemical analysis, enzyme linked immunosorbent assay, fluorescence immunohistochemistry, Western blot, and reverse transcriptase polymerase chain reaction. RESULTS: Forty-nine days' ethanol consumption induced the increases in circulating noradrenaline metabolite (3-methoxy-4-hydroxyphenylglycol), hepatic noradrenaline and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, the down-regulation of hepatic insulin receptor substrate-1 gene expression, and the accumulation of fatty droplets within hepatocytes with the increased hepatic triglyceride and blood alanine aminotransferase levels. All of these changes were modified by carvedilol treatment. 8-OHdG was detected in activated HSCs and suppressed by carvedilol treatment based on fluorescence immunohistochemical double-staining analysis. CONCLUSIONS: Carvedilol may modify the interaction between the oxidative stress and the sympathetic hyperactivity, and then contribute to attenuate the development of AFLD in rats. Additionally, oxidative stress may be responsible for the activation of HSCs during the early stage of alcoholic liver disease.
    Hepatology Research 04/2013; · 2.07 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta-blockers decrease the incidence and growth of hepatocellular carcinoma via a reduction of the inflammatory load from the gut to the liver and inhibition of angiogenesis. Due to their effect on the portal pressure, non-selective beta-blockers are used for prevention of esophageal variceal bleeding. Recently, non-hemodynamic effects of beta-blockers have received increasing attention. Blockage of β-adrenoceptors in the intestinal mucosa and gut lymphatic tissue together with changes in type and virulence of the intestinal microbiota lead to reduced bacterial translocation and a subsequent decrease in the portal load of pathogen-associated molecular patterns. This may reduce hepatic inflammation. Blockage of β-adrenoceptors also decrease angiogenesis by inhibition of vascular endothelial growth factors. Because gut-derived inflammation and neo-angiogenesis are important in hepatic carcinogenesis, non-selective beta-blockers can potentially reduce the development and growth of hepatocellular carcinoma. Rodent and in vitro studies support the hypothesis, but clinical verification is needed. Different study designs may be considered. The feasibility of a randomized controlled trial is limited due to the necessary large number of patients and long follow-up. Observational studies carry a high risk of bias. The meta-analytic approach may be used if the incidence and mortality of hepatocellular carcinoma can be extracted from trials on variceal bleeding and if the combined sample size and follow up is sufficient.
    Medical Hypotheses 09/2013; · 1.18 Impact Factor

Full-text (2 Sources)

Available from
May 31, 2014