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Use of Pharmacological Modeling to Understand Key Questions on the GOAT Ghrelin Processing In Vivo
Author(s) -
Yang HsiuChiung,
Kuo MingShang,
Tong Jenny,
Reynolds Nichole,
Shockley Travis,
Chen Yanyun,
Mosior Marian
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb521
Subject(s) - ghrelin , orexigenic , in vivo , knockout mouse , peptide , enzyme , endocrinology , biology , medicine , chemistry , pharmacology , biochemistry , gene , neuropeptide , hormone , microbiology and biotechnology , receptor , neuropeptide y receptor
Ghrelin (AG) is the only known orexigenic peptide in human and rodents. It is converted from its precursor, unacylated ghrelin (UAG), to the biologically active peptide, acylghrelin. Two independent groups (Yang et al., 2008; Gutierrez 2009) using different approaches identified the same protein, named GOAT ( G hrelin O ‐ A cyl T ransferase), as the long sought enzyme which is responsible for the bioactivation of ghrelin peptide. Results from GOAT gene knockout mice confirmed that GOAT is the principal enzyme which is responsible for the acylation of ghrelin. We have developed a GOAT enzymatic assay. Using this assay, we have demonstrated the detailed molecular mechanism of the GOAT enzymatic reaction. In addition, we used genetic and pharmacologic data to build a model for GOAT/ghrelin processing in mouse. We also used plasma acylghrelin and desacylghrelin profiles from human volunteers, following three doses of acylghelin infusion, to enrich this model and improve understanding of the dynamics of ghrelin processing in humans. We will present the ghrelin processing models for human and mouse, as well as how we use these models to answer key questions regarding ghrelin metabolism and regulation. Our data suggest that plasma unacylated ghrelin is secreted from the stomach, and not generated through deacylation in the plasma.