Abstract
Destruction of Kupffer cells with gadolinium chloride (GdCl(3)) and intestinal sterilization with antibiotics diminished ethanol-induced steatosis in the enteral ethanol feeding model. However, mechanisms of ethanol-induced fatty liver remain unclear. Accordingly, the role of Kupffer cells in ethanol-induced fat accumulation was studied. Rats were given ethanol (5 g/kg body wt) intragastrically, and tissue triglycerides were measured enzymatically. Kupffer cells were isolated 0-24 h after ethanol, and PGE(2) production was measured by ELISA, whereas inducible cyclooxygenase (COX-2) mRNA was detected by RT-PCR. As expected, ethanol increased liver triglycerides about threefold. This increase was blunted by antibiotics, GdCl(3), the dihydropyridine-type Ca(2+) channel blocker nimodipine, and the COX inhibitor indomethacin. Ethanol also increased PGE(2) production by Kupffer cells about threefold. This increase was also blunted significantly by antibiotics, nimodipine, and indomethacin. Furthermore, tissue triglycerides were increased about threefold by PGE(2) treatment in vivo as well as by a PGE(2) EP(2)/EP(4) receptor agonist, whereas an EP(1)/EP(3) agonist had no effect. Moreover, permeable cAMP analogs also increased triglyceride content in the liver significantly. We conclude that PGE(2) derived from Kupffer cells, which are activated by ethanol, interacts with prostanoid receptors on hepatocytes to increase cAMP, which causes triglyceride accumulation in the liver. This mechanism is one of many involved in fatty liver caused by ethanol.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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8-Bromo Cyclic Adenosine Monophosphate / pharmacology
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Animals
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Anti-Bacterial Agents / pharmacology
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Bucladesine / pharmacology
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Calcium Channel Blockers / pharmacology
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Cells, Cultured
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Central Nervous System Depressants / toxicity
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Culture Media, Conditioned / pharmacology
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Cyclic AMP / metabolism
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology
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Dinoprostone / biosynthesis*
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Dinoprostone / pharmacology
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Ethanol / toxicity
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Fatty Liver / metabolism*
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Fatty Liver / pathology
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Female
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Gene Expression Regulation, Enzymologic
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Indomethacin / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / genetics
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Isoenzymes / pharmacology
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Kupffer Cells / cytology
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Kupffer Cells / enzymology*
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Lipopolysaccharides / pharmacology
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Liver Cirrhosis, Alcoholic / metabolism*
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Liver Cirrhosis, Alcoholic / pathology
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Nimodipine / pharmacology
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Oligonucleotide Probes
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Organ Size
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Prostaglandin-Endoperoxide Synthases / genetics
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Prostaglandin-Endoperoxide Synthases / pharmacology
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RNA, Messenger / analysis
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Rats
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Rats, Sprague-Dawley
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Triglycerides / metabolism
Substances
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Anti-Bacterial Agents
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Calcium Channel Blockers
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Central Nervous System Depressants
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Culture Media, Conditioned
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Isoenzymes
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Lipopolysaccharides
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Oligonucleotide Probes
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RNA, Messenger
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Triglycerides
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8-Bromo Cyclic Adenosine Monophosphate
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Ethanol
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Nimodipine
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Bucladesine
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Cyclic AMP
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Cyclooxygenase 2
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Prostaglandin-Endoperoxide Synthases
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Dinoprostone
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Indomethacin