Ascorbic acid suppresses endotoxemia and NF-κB signaling cascade in alcoholic liver fibrosis in guinea pigs: a mechanistic approach.
Alcohol consumption increases the small intestinal bacterial overgrowth (SIBO) and intestinal permeability of endotoxin. The endotoxin mediated inflammatory signaling plays a major role in alcoholic liver fibrosis. We evaluated the effect of ascorbic acid (AA), silymarin and alcohol abstention on the alcohol induced endotoxemia and NF-κB activation cascade pathway in guinea pigs (Cavia porcellus). Guinea pigs were administered ethanol at a daily dose of 4g/kg b.wt for 90days. After 90days, ethanol administration was stopped. The ethanol treated animals were divided into abstention, silymarin (250mg/kg b.wt) and AA (250mg/kg b.wt) supplemented groups and maintained for 30days. The SIBO, intestinal permeability and endotoxin were significantly increased in the ethanol group. The mRNA expressions of intestinal proteins claudin, occludin and zona occludens-1 were significantly decreased in ethanol group. The mRNA levels of inflammatory receptors, activity of IKKβ and the protein expressions of phospho-IκBα, NF-κB, TNF-α, TGF-β1 and IL-6 were also altered in ethanol group. The expressions of fibrosis markers α-SMA, α1 (I) collagen and sirius red staining in the liver revealed the induction of fibrosis. But the supplementation of AA could induce greater reduction of ethanol induced SIBO, intestinal barrier defects, NF-κB activation and liver fibrosis than silymarin. The possible mechanism may be the inhibitory effect of AA on SIBO, intestinal barrier defect and IKKβ, which decreased the activation of NF-κB and synthesis of cytokines. This might have led to suppression of HSCs activation and liver fibrosis.
Department of Biochemistry, University of Kerala, Kariavattom, Thiruvananthapuram 695 581, Kerala, India.
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Abhilash
Department of Biochemistry, University of Kerala, Kariavattom, Thiruvananthapuram 695 581, Kerala, India.
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Harikrishnan
Department of Biochemistry, University of Kerala, Kariavattom, Thiruvananthapuram 695 581, Kerala, India. Electronic address: indiramadambath@gmail.com.
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Indira
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D057167:Claudins / Q000235:genetics / Q000378:metabolism; D019446:Endotoxemia / Q000188:drug therapy*; D004731:Endotoxins / Q000378:metabolism / Q000633:toxicity; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects; D006168:Guinea Pigs; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000382:microbiology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008104:Liver Cirrhosis, Alcoholic / Q000188:drug therapy*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012838:Silymarin / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
D057167:Claudins; D004731:Endotoxins; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D062793:Occludin; D012333:RNA, Messenger; D012838:Silymarin; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D062826:Zonula Occludens-1 Protein; D000072000:NF-KappaB Inhibitor alpha; D000431:Ethanol; D001205:Ascorbic Acid
Alcohol; Ascorbic acid; Guinea pigs; Hepatocytes; Liver toxicity