CCK-induced pancreatic growth is not limited by mitogenic capacity in mice

Abstract

In mice fed trypsin inhibitor (camostat) to elevate endogenous CCK, pancreatic growth plateaus by 7 days. It is unknown whether this represents the maximum growth capacity of the pancreas. To test the ability of CCK to drive further growth, mice were fed chow containing camostat (0.1%) for 1 wk, then fed standard chow for 1 wk, and finally returned to the camostat diet for a week. Pancreatic mass increased to 245% of initial value (iv) following 1 wk of camostat feeding, decreased to 147% iv following a 1 wk return to normal chow, and increased to 257% iv with subsequent camostat feeding. Camostat feeding was associated with significant increases in circulating CCK and changes in pancreatic mass were paralleled by changes in protein and DNA content. Moreover, regression of the pancreas following camostat feeding was associated with changes in the expression of the autophagosome marker LC3. Pancreatic protein synthetic rates were 130% of control after 2 days on camostat but were equivalent to control after 7 days. Changes in the phosphorylation of 4E-BP1 and S6, downstream effectors of mammalian target of rapamycin (mTOR), paralleled changes in protein synthetic rates. Cellular content of Akt, an upstream activating kinase of mTOR, decreased after 7 days of camostat feeding whereas expression of the E3 ubiquitin-ligases and the cell cycle inhibitor p21 increased after 2 days. These results indicate that CCK-stimulated growth of the pancreas is not limited by acinar cell mitogenic capacity but is due, at least in part, to inhibition of promitogenic Akt signaling.

CCK-independent mTORC1 activation during dietary protein-induced exocrine pancreas growth

“…CCK-induced pancreatic growth is associated with activation of the PI3K-Akt-mTORC1 pathway (4,8,9,34). In the present study, feeding normalprotein chow for 2 h following 16 h of food deprivation resulted in statistically significant increases in the phosphorylation of Akt (Fig.…”

Regulator of Calcineurin 1 Controls Growth Plasticity of Adult Pancreas

“…As an additional control, we examined the effect of feeding. In fasted mice circulating CCK is typically at 0.5–1 pM, in animals fed standard diet it increases to 3–5 pM, whereas in those fed PI-containing chow to ~15 pM16. No appreciable increase in Rcan1 expression was noted among feeding controls or CCK-deficient mice (Figure 3D).…”

“…Determination of body weight, protein, DNA concentration and BrdU-based acinar cell proliferation were performed as previously described16. DAPI-stained nuclei were quantified using CellProfiler ™ software per authors’ instructions17, whereas BrdU-positive cells were counted by hand.…”

ADP-ribosylation Factor 1 Protein Regulates Trypsinogen Activation via Organellar Trafficking of Procathepsin B Protein and Autophagic Maturation in Acute Pancreatitis

“…Although recent studies suggest a role for autophagy (16) or its derangement (10) in the generation of intracellular trypsin, the induction of autophagy (e.g. by fasting (47) or cessation of camostat feeding (48)) results in pancreatic atrophy (47) but not in pancreatitis or the generation of trypsin (10). Interestingly, Nevalainen and Janigan (47) did not find zymogen granules in autophagosomes generated during fasting.…”