Extracelullar Proteolysis of the Hormone Ghrelin Generates a Specific Subset of Ghrelin-Derived Peptides with Differential Bioactivities

DANIELA LUFRANO; NICOLAS DE FRANCESCO; ANTONELA FITTIPALDI; GIMENA FERNANDEZ; DANIEL CASTROGIOVANNI; MARIO PERELLO; SEBASTIAN TREJO

Congreso; Reunión Anual de Sociedades de Biociencia; 2019

The stomach-derived hormone ghrelin is a peptide of 28 residues acylated with an octanoic acid at Ser3. The N-terminal sequence of ghrelin along with the octanoyl group are essential to act on the ghrelin receptor. Here, we tested the hypothesis that ghrelin can be extracelullarly cleaved in order to generate ghrelin-derived peptides with differential bioactivities. Initially, we incubated ghrelin with plasma and then performed MALDI-TOF MS analysis. We found that ghrelin is mainly cleaved in the region extended from residue 11 to 16. Then, we incubated ghrelin with liver carcinoma HepG2 cells or with extracelullar medium derived from these cells, and also found that ghrelin cleavage occurs in the same ?hot cleavage region? of its sequence. Since ghrelin1-11 and ghrelin1-14 were derived from ghrelin proteolysis, we then tested the ability of these shorter versions of ghrelin to act in the brain and stimulate appetite in mice. We found that ghrelin1-11 and ghrelin1-14 were unable to induce neuronal activation, assessed by the marker of neuronal activation c-Fos, nor to increase food intake; however, these shorter versions of ghrelin seem to impair the orexigenic effect of full-length ghrelin. Thus, these data support the existence of a proteolytic extracelullar mechanism that generates ghrelin-derived peptides with different bioactivity than full-length ghrelin. Moreover, the liver may be involved in this mechanism during the passage of ghrelin through the hepatic portal circulation.