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G Kenth, Experimental Medicine, McGill University, Montreal, Quebec, Canada
J Mergelas, Experimental Medicine, McGill University, Montreal, Quebec, Canada
C Goodyer, Pediatrics, McGill University, Montreal, Quebec, Canada

Correspondence: Cynthia Goodyer, Email: cindy.goodyer{at}muhc.mcgill.ca

Abstract

We previously reported the presence of functional hGH receptors (hGHR) in the human fetal hepatocyte (FH) as early as the first trimester. Interestingly, fetal serum levels of hGH are in the acromegalic range yet certain hGH-dependent factors are expressed at very low levels (IGF-1, IGFBP-3), suggesting that the fetal liver has limited responsiveness to hGH. To determine whether this is due to the fetal tissue levels of hGHR or factors in the hGH/hGHR axis that might influence hGHR function, we compared hGHR isoforms and downstream signaling proteins in FH vs. adult liver (HAL). Immunoprecipitation/immunoblotting analyses found similar precursor and mature hGHR forms while RT-PCR assays of truncated (T) hGHR1-279, a dominant negative for the full-length (FL) receptor, showed similar T/FL mRNA ratios in FH and HAL. Immunoblotting demonstrated that JAK2, STAT(1,3,5A/B) and SOCS(1,2,3,CIS) proteins were detectable in all FH and HAL tested (12wk fetal age to 60yr); levels were similar (STAT5B) or lower (JAK2/STAT1/3/5A: 38-53%; SOCS/CIS: 58-76%) in FH compared to HAL.

Our studies to date demonstrate that, during hepatocyte development, hGHR levels are lower in the fetal cells but the hGHR isoforms, including the relative amount of truncated vs. full-length, remain unchanged. The JAK2/STAT/SOCS signaling molecules are present in the fetal hepatocyte as early as the first trimester. However, they are generally at <50% the level in postnatal liver. These data suggest that low expression of both hGHR and major hGHR signaling components may explain the limited responsiveness of the fetal cells to the high circulating levels of hGH.