The lipase C-terminal domain. A novel unusual inhibitor of pancreatic lipase activity.
In vertebrates, dietary fat digestion mainly results from the combined effect of pancreatic lipase, colipase, and bile. It has been proposed that in vivo lipase adsorption on oil-water emulsion is mediated by a preformed lipase-colipase-mixed micelle complex. The main lipase-colipase binding site is located on the C-terminal domain of the enzyme. We report here that in vitro the isolated C-terminal domain behaves as a potent noncovalent inhibitor of lipase and that the inhibitory effect is triggered by the presence of micelles. Lipase inhibition results from the formation of a nonproductive C-terminal domain-colipase-micelle ternary complex, which competes for colipase with the active lipase-colipase-micelle ternary complex, thus diverting colipase from its lipase-anchoring function. The formation of such a complex has been evidenced by molecular sieving experiments. This nonproductive complex lowers the amount of active lipase thus reducing lipolysis. Preliminary experiments performed in rats show that the C-terminal domain also behaves as an inhibitor in vivo and thus could be considered a potential new tool for specifically reducing intestinal lipolysis.
Ayvazian
L
L
INSERM -U476 Nutrition Humaine et Lipides, 18 Avenue Mozart 13009 Marseille, France.
Kerfelec
B
B
Granon
S
S
Foglizzo
E
E
Crenon
I
I
Dubois
C
C
Chapus
C
C
D000818:Animals; D001665:Binding Sites; D002850:Chromatography, Gel; D003089:Colipases / Q000737:chemistry / Q000302:isolation & purification; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008049:Lipase / Q000737:chemistry* / Q000302:isolation & purification; D008297:Male; D008823:Micelles; D008958:Models, Molecular; D010179:Pancreas / Q000201:enzymology*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D003089:Colipases; D004791:Enzyme Inhibitors; D008823:Micelles; D008049:Lipase