Rôle de l'endocytose dans la protéolyse de l'insuline et du glucagon dans l'hépatocyte

Abstract

The major hormones regulating glucose homeostasis are and glucagon. The islets of Langerhans in the pancreas are anatomically positioned to deliver these hormones to the portal circulation of the liver. Insulin and glucagon secreted from the pancrease are extracted from; the portal circulation to the extent of > 45 % in a single pass through the liver. Liver clearance of these:pancreatic hormones is effected mainly by a receptor-mediated mechanism. After binding to the hepatic plasmalemma, hormone/ receptor complexes are rapidly internalized into components of the endosomal apparatus, inside which a progressive degradation of internalized hormones has been demonstrated. ATP-dependent acidification is required for optimal degradation of insulin and glucagon within endosomes by distinct proteinases whose nature remains undefined. It has been recently shown that the insulin and glucagon proteinases within endosomes display an acidic pH optimum and are unrelated to insulin degrading enzyme (IDE), a cytosolic thiol-metalloprotease proposed previously to be the main cellular clearance mechanism. This latter enzyme has been observed in peroxisomes and indeed possesses a classical A/SKL peroxisomal targeting motif at its extreme carboxy termini and is unlikely to be relevant to hormone degradation in vivo. Since ligand degradation is an important process for control of hormone action, the endosomal hormone degrading proteinases that we have identified may be clinically relevant and may represent important potential targets for pharmaceutical agents which control hormone action.