The in vivo metabolism of cholecystokinin (CCK-8) is essentially ensured by aminopeptidase A

Migaud, Martine; Durieux, Christiane; Viereck, Jason; Soroca-Lucas, Evelyne; Fournié‐Zaluski, Marie‐Claude; Roques, Bernárd P.

doi:10.1016/0196-9781(96)00036-8

Cited by 65 publications

(35 citation statements)

References 38 publications

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“…Plasmamediated degradation of CCK is poorly understood and a number of enzymes have been postulated to be involved [14]. Thus, the use of enzyme inhibitors to prolong the biological action of CCK is fraught with difficulties [15]. A more specific approach would therefore be to generate enzymatic-resistant analogues of CCK to extend the biological half-life of the peptide.…”

Section: Introductionmentioning

confidence: 99%

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

et al. 2012

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Aims/hypothesis Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8. Methods The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice. Results (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p<0.05 to p<0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p<0.01 to p<0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p<0.05 to p<0.001), accumulated food intake (p< 0.05 to p<0.001), non-fasting glucose (p<0.05) and triacylglycerol deposition in pancreatic (p<0.01), adipose (p< 0.05) and liver (p<0.001) tissue, and improved oral (p< 0.05) and i.p. (p<0.05) glucose tolerance and insulin sensitivity (p<0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology. Conclusions/interpretation These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.

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Section: Introductionmentioning

confidence: 99%

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

et al. 2012

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“…APA is involved in i o in the conversion of brain angiotensin II into angiotensin III [2] and in the metabolism of cholecystokinin-8 [3]. The enzyme is also the major intestinal zinc metallopeptidase responsible for the metabolism of the artificial sweetener aspartame [4].…”

Section: Introductionmentioning

confidence: 99%

The C-terminal domain, but not the interchain disulphide, is required for the activity and intracellular trafficking of aminopeptidase A

Ofner¹,

Hooper²

2002

Biochem. J.

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“…The Aminopeptidase A (APA) ectopeptidase is a integral membrane-bound member of the zinc metalloprotease family (Jongeneel, et al, 1989;Wu, et al, 1990) that cleaves aspartic or glutamic acidic residues from the N-terminus of a large variety of protein substrates, including angiotensin II (Wolf, et al, 1997;Zini, et al, 1996), cholecystokinin-8 (Migaud, et al, 1996), neurokinin B and chromogranin A (Goto, et al, 2006) as part of their respective metabolic pathways. The protein consists of 3 domains; a 17-amino acid cytosolic N-terminal domain, a 22 amino acid transmembrane hydrophobic domain and a 906 amino acid extracellular Cterminal domain (Li, et al, 1993;Nanus, et al, 1993;Wu, et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Functional genetic variation in aminopeptidase A (ENPEP): Lack of clear association with focal and segmental glomerulosclerosis (FSGS)

Tonna

Dandapani

Uscinski

et al. 2008

Gene

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The aminopeptidase A (APA) ectopeptidase is an integral membrane-bound zinc metalloprotease that cleaves aspartic and glutamic acidic residues from the N-terminus of a number of protein substrates that includes angiotensin II. Angiotensin II, the most vasoactive component of the reninangiotensin-aldosterone (RAAS) pathway, can contribute to renal disease by causing an increase in arterial blood pressure leading to glomerular injury and fibrosis. APA is expressed in many organs, including the kidney where it localizes mainly to the podocyte cell membrane and brush borders of the proximal tubule cells. Antibodies directed to the APA peptide can induce an acute massive albuminuria in wild type BALB/c mice after intravenous injection.We examined whether variants in the APA encoding gene (ENPEP) are more frequent in individuals with the proteinuric disease focal and segmental glomerulosclerosis (FSGS) compared to control individuals. The ENPEP coding sequence was resequenced in 188 FSGS patients and 48 controls. Genetic variants were further genotyped in 181 individuals without any known kidney disease. We then examined the effect of the non-synonymous coding variants identified on their cell surface APA activity after transfection in COS-1 cells.Several of these ENPEP variants lead to reproducibly altered APA activity. However, we did not see a clear correlation between the presence of a functional ENPEP variant and FSGS. However, the existence of these variants with marked effect on APA activity suggests that both rare and common variation in ENPEP may contribute to the development of renal and hypertensive disorders and warrants further study.

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The in vivo metabolism of cholecystokinin (CCK-8) is essentially ensured by aminopeptidase A

Cited by 65 publications

References 38 publications

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

The C-terminal domain, but not the interchain disulphide, is required for the activity and intracellular trafficking of aminopeptidase A

Functional genetic variation in aminopeptidase A (ENPEP): Lack of clear association with focal and segmental glomerulosclerosis (FSGS)

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