title: Melanocortin receptors in rat liver cells: change of gene expression and intracellular localization during acute-phase response.
abstract: MCRs are known to be expressed predominantly in the brain where they mediate metabolic and anti-inflammatory functions. Leptin plays an important role in appetite and energy regulation via signaling through melanocortin receptors (MCRs) in the brain. As serum levels of MCR ligands are elevated in a clinical situation [acute-phase response (APR)] to tissue damage, where the liver is responsible for the metabolic changes, we studied hepatic gene expression of MCRs in a model of muscle tissue damage induced by turpentine oil (TO) injection in rats. A significant increase in gene expression of all five MCRs (MC4R was the highest) in liver at the RNA and protein level was detected after TO injection. A similar pattern of increase was also found in the brain. Immunohistology showed MC4R in the cytoplasm, but also in the nucleus of parenchymal and non-parenchymal liver cells, whereas MC3R-positivity was mainly cytoplasmic. A time-dependent migration of MC4R protein from the cytoplasm into the nucleus was observed during APR, in parallel with an increase in α-MSH and leptin serum levels. An increase of MC4R was detected at the protein level in wild-type mice, while such an increase was not observed in IL-6ko mice during APR. Moreover, treatment of isolated liver cells with melanocortin agonists (α-MSH and THIQ) inhibited the endotoxin-induced upregulation of the acute-phase cytokine (IL-6, IL1β and TNF-α) gene expression in Kupffer cells and of chemokine gene expression in hepatocytes. MCRs are expressed not only in the brain, but also in liver cells and their gene expression in liver and brain tissue is upregulated during APR. Due to the presence of specific ligands in the serum, they may mediate metabolic changes and exert a protective effect on liver cells.
authors.affiliation: Division of Gastroenterology and Endocrinology, Department of Internal Medicine, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
authors.forename: Ihtzaz Ahmed
authors.initials: IA
authors.lastname: Malik
authors.forename: Jakob
authors.initials: J
authors.lastname: Triebel
authors.forename: Jessica
authors.initials: J
authors.lastname: Posselt
authors.forename: Sajjad
authors.initials: S
authors.lastname: Khan
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Ramadori
authors.forename: Dirk
authors.initials: D
authors.lastname: Raddatz
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ramadori
mesh_terms: D000210:Acute-Phase Reaction / Q000276:immunology*; D000818:Animals; D001921:Brain / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology; D020738:Leptin / Q000097:blood; D008099:Liver / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics / Q000276:immunology; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics / Q000276:immunology; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics / Q000276:immunology; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000276:immunology; D044101:Receptors, Melanocortin / Q000235:genetics* / Q000276:immunology*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D000521:alpha-MSH / Q000097:blood / Q000494:pharmacology
chemical_list: D015850:Interleukin-6; D020738:Leptin; C467221:N-(1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl)-1-(4-chlorobenzyl)-2-(4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl)-2-oxoethylamine; D044102:Receptor, Melanocortin, Type 1; D044103:Receptor, Melanocortin, Type 2; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D044101:Receptors, Melanocortin; D044005:Tetrahydroisoquinolines; D014230:Triazoles; C086971:melanocortin 5 receptor; D000521:alpha-MSH