Identification of the Acyltransferase that Octanoylates Ghrelin, an Appetite-Stimulating Peptide Hormone

Abstract

Ghrelin is a 28 amino acid, appetite-stimulating peptide hormone secreted by the food-deprived stomach. Serine-3 of ghrelin is acylated with an eight-carbon fatty acid, octanoate, which is required for its endocrine actions. Here, we identify GOAT (Ghrelin O-Acyltransferase), a polytopic membrane-bound enzyme that attaches octanoate to serine-3 of ghrelin. Analysis of the mouse genome revealed that GOAT belongs to a family of 16 hydrophobic membrane-bound acyltransferases that includes Porcupine, which attaches long-chain fatty acids to Wnt proteins. GOAT is the only member of this family that octanoylates ghrelin when coexpressed in cultured endocrine cell lines with prepro-ghrelin. GOAT activity requires catalytic asparagine and histidine residues that are conserved in this family. Consistent with its function, GOAT mRNA is largely restricted to stomach and intestine, the major ghrelin-secreting tissues. Identification of GOAT will facilitate the search for inhibitors that reduce appetite and diminish obesity in humans.

Ghrelin in obesity and endocrine diseases

“…This post-translational modification is mediated by ghrelin O-acyltransferase (GOAT) (Yang et al, 2008) and is essential for GHS-R1a activation and the endocrine actions of ghrelin (Kojima & Kangawa, 2005). Consistent with its function, GOAT mRNA is primarily limited to the stomach; the main ghrelin-secreting tissue (Yang et al, 2008). Acylated ghrelin induces body weight gain and adiposity by promoting food intake and decreasing energy expenditure (Asakawa et al, 2005;Tschop et al, 2000).…”

“…GOAT has been implicated as another potential target for the development of anti-obesity treatment (Gualillo et al, 2008;Yang et al, 2008). Chronic treatment of mice on a high fat diet with GO-CoA-Tat, a peptide-based GOAT inhibitor, prevented the significant weight gain observed in vehicle-treated controls.…”

Lipopolysaccharide Increases Gastric and Circulating NUCB2/Nesfatin-1 Concentrations in Rats

“…We reported previously that LPS markedly reduces fasting plasma levels of total ghrelin in rats [4,39] and extended these observations by showing that plasma acyl ghrelin is more rapidly suppressed compared to desacyl ghrelin resulting in a reduced acyl/desacyl ghrelin ratio at 2 h post LPS injection [31]. This was associated with a decrease of plasma ghrelin-O-acyltransferase (GOAT), the recently identified ghrelin acylating enzyme [44], whereas gastric GOAT protein concentration was increased [31].…”

Acylated and unacylated ghrelin do not directly stimulate glucose transport in isolated rodent skeletal muscle

“…2008; Yang et al. 2008; Satou and Sugimoto 2012). It exists primarily unbound and unacylated, although many of ghrelin's effects can be attributed to its acylated form (Patterson et al.…”