期刊
MOLECULAR ENDOCRINOLOGY
卷 22, 期 6, 页码 1427-1437出版社
OXFORD UNIV PRESS INC
DOI: 10.1210/me.2007-0561
关键词
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资金
- NCI NIH HHS [P30 CA-13148-34, P30 CA013148] Funding Source: Medline
- NIDDK NIH HHS [DK49845, R01 DK058259, DK58259, R01 DK049845, R56 DK049845, K08 DK002700, R01 DK002700, R29 DK049845, DK02700, R56 DK058259] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [P30CA013148] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K08DK002700, R01DK049845, R01DK002700, R01DK058259, R56DK049845, R56DK058259, R29DK049845, R37DK002700] Funding Source: NIH RePORTER
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 wildtype 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.
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