title: Endotoxin-induced proteolytic reduction in hepatic growth hormone (GH) receptor: a novel mechanism for GH insensitivity.
abstract: GH is an important anabolic hormone. We previously demonstrated in cell culture that the cell surface GH receptor (GHR) is susceptible to inducible metalloproteolytic cleavage that yields the shed receptor extracellular domain (called GH binding protein) and renders the cells desensitized to subsequent GH stimulation. Sepsis and inflammatory states are associated with hepatic desensitization to GH, although disparate mechanisms have been postulated in various animal models. Using C3H/HeJ mice, we now demonstrate that administration of lipopolysaccharide (LPS) causes marked hepatic desensitization to GH, assessed by monitoring signal transducer and activator of transcription 5 tyrosine phosphorylation and nuclear accumulation and with a novel noninvasive bioluminescence imaging system to track in vivo hepatic GH signaling serially in individual mice. This endotoxin-induced desensitization was accompanied by marked loss of hepatic GHR, which was not explained by changes in GHR mRNA abundance. Furthermore, we observe that LPS causes GH-binding protein shedding of a hepatically expressed wild-type GHR but not a GHR with a mutation in the metalloprotease cleavage site. These data suggest that in this model system, LPS-induced desensitization to GH is associated with proteolytic GHR cleavage. These data are the first to demonstrate inducible in vivo GHR proteolysis and suggest this is a mechanism to regulate GH sensitivity and its anabolic effects during sepsis or inflammation.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0012, USA.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Jiang
authors.forename: Jason
authors.initials: J
authors.lastname: Warram
authors.forename: Gerhard
authors.initials: G
authors.lastname: Baumann
authors.forename: Yujun
authors.initials: Y
authors.lastname: Gan
authors.forename: Ram K
authors.initials: RK
authors.lastname: Menon
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Zinn
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Frank
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004351:Drug Resistance / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology*; D005260:Female; D013006:Growth Hormone / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017978:Receptors, Growth Factor / Q000378:metabolism* / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D004731:Endotoxins; D008070:Lipopolysaccharides; D017978:Receptors, Growth Factor; D050799:STAT5 Transcription Factor; D013006:Growth Hormone; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C051815:somatotropin-binding protein