Glucose and Weight Control in Mice with a Designed Ghrelin O-Acyltransferase Inhibitor

Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Science (Impact Factor: 33.61). 12/2010; 330(6011):1689-92. DOI: 10.1126/science.1196154
Source: PubMed


Ghrelin is a gastric peptide hormone that stimulates weight gain in vertebrates. The biological activities of ghrelin require
octanoylation of the peptide on Ser3, an unusual posttranslational modification that is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). Here, we describe
the design, synthesis, and characterization of GO-CoA-Tat, a peptide-based bisubstrate analog that antagonizes GOAT. GO-CoA-Tat
potently inhibits GOAT in vitro, in cultured cells, and in mice. Intraperitoneal administration of GO-CoA-Tat improves glucose
tolerance and reduces weight gain in wild-type mice but not in ghrelin-deficient mice, supporting the concept that its beneficial
metabolic effects are due specifically to GOAT inhibition. In addition to serving as a research tool for mapping ghrelin actions,
GO-CoA-Tat may help pave the way for clinical targeting of GOAT in metabolic diseases.

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    • ". ghrelin o-acyltransferase (goAt): GOAT has been regarded as an orphan member of a family of membrane-bound Oacyltransferase enzymes (MBOATs) and is the only known enzyme that has a capacity to acetylate ghrelin. This membrane-bound enzyme can transfer octanoate to serine-3 of ghrelin from octanoyl CoA [35] [36] "
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    ABSTRACT: Abstract Background: Ghrelin is a type of growth hormone (GH) secretagogue that stimulates the release of growth hormone (GH). It is a first hormone linking gastrointestinal-pituitary axis. Objective: This review highlights the interaction of ghrelin with GHRH and somatostatin to regulate the secretion of GH and intends to explore the possible physiological role of the ghrelin-pituitary-GH axis linkage system. Observation: Ghrelin is highly conserved among species and is classified into octanoylated (C8:0), decanoylated (C10:0), decenoylated (C10:1) and nonacylated,ghrelin. Acylated ghrelin is the major active form of human ghrelin. The primary production site of ghrelin is the stomach, and it interacts with stomach ghrelin as well as hypothalamic GHRH and somatostatin in the regulation of pituitary GH secretion. Ghrelin stimulate GH release through the GHS receptor to increase intracellular Ca2+ ([Ca2+] levels via IP3 signal transduction pathway. Ghrelin is a specific endogenous ligand for the GHS receptor and provides a definitive proof of the occurance of a GHS–GHS receptor signalling system in the regulation of GH secretion. Conclusion: Studies suggests that ghrelin is a powerful pharmacological agent that exerts a potent, time-dependent stimulation of pulsatile secretion of GH. Keywords : Ghrelin, Growth Hormone, Ghrelin-Pituitary-Gh Axis Linkage System
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    • "These compounds affect Shh signaling in model in vitro assays although effects on the growth of tumour cells were not reported. In addition, two selective small molecule inhibitors of the Porc MBOAT member have been described [45], [46] which inhibit Wnt acylation and do not affect Hhat, and inhibitors of GOAT have also been reported [47], [48]. The Porc inhibitor C59 inhibited the growth of a Wnt-driven breast cancer cell line and Wnt signaling, both in vitro and in a mouse xenograft model, with no apparent toxicity in the mice [46]. "
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    ABSTRACT: Overexpression of Hedgehog family proteins contributes to the aetiology of many cancers. To be highly active, Hedgehog proteins must be palmitoylated at their N-terminus by the MBOAT family multispanning membrane enzyme Hedgehog acyltransferase (Hhat). In a pancreatic ductal adenocarcinoma (PDAC) cell line PANC-1 and transfected HEK293a cells Hhat localized to the endoplasmic reticulum. siRNA knockdown showed that Hhat is required for Sonic hedgehog (Shh) palmitoylation, for its assembly into high molecular weight extracellular complexes and for functional activity. Hhat knockdown inhibited Hh autocrine and juxtacrine signaling, and inhibited PDAC cell growth and invasiveness in vitro. In addition, Hhat knockdown in a HEK293a cell line constitutively expressing Shh and A549 human non-small cell lung cancer cells inhibited their ability to signal in a juxtacrine/paracrine fashion to the reporter cell lines C3H10T1/2 and Shh-Light2. Our data identify Hhat as a key player in Hh-dependent signaling and tumour cell transformed behaviour.
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    • "). Therefore, due to this crucial role of AG in the regulation of pancreas and insulin physiology, it has been suggested that GHSR blockers and/or GOAT inhibitors might be used as putative antidiabetic drugs in the future (Gualillo et al. 2008, Barnett et al. 2010). "
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