Faculty Collaboration Database

Regulation of liver hepcidin expression by alcohol in vivo does not involve Kupffer cell activation or TNF-alpha signaling. Am J Physiol Gastrointest Liver Physiol 2009 Jan;296(1):G112-8

Date

11/15/2008

Pubmed ID

19008338

Pubmed Central ID

PMC3833991

DOI

10.1152/ajpgi.90550.2008

Scopus ID

2-s2.0-58249117786 (requires institutional sign-in at Scopus site)   19 Citations

Abstract

Alcohol downregulates hepcidin expression in the liver leading to an increase in intestinal iron transport and liver iron storage. We have previously demonstrated that alcohol-mediated oxidative stress is involved in the inhibition of hepcidin transcription by alcohol in vivo. Kupffer cells and TNF-alpha play a key role in alcohol-induced liver injury. The aim of this study was to define their involvement in the regulation of hepcidin expression by alcohol. Kupffer cells were inactivated or depleted by employing gadolinium chloride and liposomes containing clodronate, respectively. Rats pair fed with the alcohol-Lieber-DeCarli diet for 6 wk and mice fed with 20% ethanol in the drinking water for 1 wk were used as experimental models. Interestingly, alcohol downregulated hepcidin expression in the livers of rats and mice independent of gadolinium chloride or clodronate treatment. One week of alcohol treatment was sufficient to induce a significant increase in TNF-alpha levels and phosphorylation of NF-kappaB subunit p65. The neutralization of TNF-alpha by specific antibodies inhibited p65 phosphorylation. However, neither the neutralization of TNF-alpha nor the lack of TNF-alpha receptor expression reversed alcohol-induced suppression of liver hepcidin expression. The level of alcohol-induced ROS in the liver was also undiminished following Kupffer cell inactivation or depletion. Our results demonstrate that alcohol-induced Kupffer cell activation and TNF-alpha signaling are not involved in the suppression of liver hepcidin expression by alcohol-mediated oxidative stress in vivo. Therefore, these findings suggest that alcohol acts within hepatocytes to suppress hepcidin expression and thereby influences iron homeostasis.

Author List

Harrison-Findik DD, Klein E, Evans J, Gollan J

MESH terms used to index this publication - Major topics in bold

Alcohol Drinking
Animals
Antimicrobial Cationic Peptides
Clodronic Acid
Ethanol
Gadolinium
Hepcidins
Kupffer Cells
Liver
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxidative Stress
Phosphorylation
Rats
Rats, Wistar
Reactive Oxygen Species
Receptors, Tumor Necrosis Factor, Type I
Receptors, Tumor Necrosis Factor, Type II
Signal Transduction
Transcription Factor RelA
Tumor Necrosis Factor-alpha