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1 Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, and 2 Division of Digestive Disease and Nutrition, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365
Destruction of Kupffer cells with gadolinium chloride (GdCl3) 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 PGE2 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, GdCl3, the dihydropyridine-type Ca2+ channel blocker nimodipine, and the COX inhibitor indomethacin. Ethanol also increased PGE2 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 PGE2 treatment in vivo as well as by a PGE2 EP2/EP4 receptor agonist, whereas an EP1/EP3 agonist had no effect. Moreover, permeable cAMP analogs also increased triglyceride content in the liver significantly. We conclude that PGE2 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.
fatty liver; triglyceride; adenosine 3',5'-cyclic monophosphate; ethanol
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