Stimulation of liver RNA and protein breakdown in endotoxemic rats: role of glucocorticoids.
In systemic or localized acute inflammation, liver ribosomal RNA (rRNA) and protein contents increase. We first determined whether changes in RNA, more specifically rRNA, and protein breakdown rates were involved in the accumulation of both types of macromolecules 24 h after induction of endotoxemia. Liver RNA and protein contents were enhanced by 35 and 19%, respectively, in the endotoxemic rats. RNA and protein degradation rates measured during in situ cyclic perfusions of the livers were significantly higher in the endotoxemic rats than in the controls (42 and 46%, respectively). In order to check that the stimulation of RNA and protein degradation corresponded to an activation of the hepatocyte autophagic pathway, the fractional cytoplasmic volume (FCV) of autophagosomes, digestive autophagic vacuoles and dense bodies was measured by morphometry in electron microscopy. The FCV of the sum of these lysosomal structures was significantly increased in the endotoxemic rats. We next tried to identify the factor(s) responsible for the high breakdown rates. The increase in macromolecular degradation did not result from reduced portal amino acid supply. The effects of dexamethasone, interleukin-6, interleukin-1beta, and tumor necrosis factor alpha on RNA degradation were then investigated in primary cultures of hepatocytes isolated from control rats. Only dexamethasone stimulated RNA breakdown. Finally, pretreatment of endotoxemic rats with RU 38486, a glucocorticoid receptor antagonist, completely abolished the stimulation of RNA degradation observed in the sham-gavaged LPS-treated rats. Our data suggest an important role of glucocorticoids in the high levels of RNA and protein breakdown in endotoxemic rats.
Saadane
A
A
Laboratoire de Biologie Cellulaire, Unité 327 de l'Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine Xavier Bichat, Université Paris 7, France.
Delautier
D
D
Leboucher
J
J
Kharbajou
M
M
Feldmann
G
G
Lardeux
B
B
Bleiberg-Daniel
F
F
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism / Q000648:ultrastructure; D003907:Dexamethasone / Q000494:pharmacology; D019446:Endotoxemia / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D008070:Lipopolysaccharides; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism*; D012313:RNA / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D000596:Amino Acids; D005938:Glucocorticoids; D006727:Hormone Antagonists; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D015735:Mifepristone; D012313:RNA; D003907:Dexamethasone