Dietary Regulation of Pancreatic Digestive Enzymes

Summary

Principal Investigator: J A Williams
Affiliation: University of Michigan
Country: USA
Abstract: The pancreas shortly after each meal secretes the majority of the enzymes required for digestion of a diverse array of dietary components. To match the amount of available digestive enzymes to digestive need, both the synthesis of digestive enzymes and the size of the gland are regulated. This is in part via the hormones and neurotransmitters that stimulate digestive enzyme secretion, particularly cholecystokinin (CCK), but also by dietary components, particularly amino acids. It is the purpose of the proposed work to characterize this regulation, uncover the molecular mechanisms, and relate the stimulatory mechanisms to the integrative response. Specific Aims of this proposal include: (1) determining the role and mechanism by which food, amino acids and CCK induce the synthesis of pancreatic digestive enzymes. We will first establish the time course and extent of enhanced pancreatic protein synthesis in mice after feeding. The state of activation of translation initiation factors, particularly elF2 and eIF4E, and p70 ribosomal S6 kinase will be evaluated. We will determine the effects of amino acids particularly leucine as a signal to initiate protein synthesis and activate the translation machinery. We will also determine the relative importance and synergy of CCK, amino acids and insulin in regulating protein synthesis. (2) We will determine the role by which CCK and amino acids enhance pancreatic growth. We will determine the effects of dietary protein in the absence of CCK on MAP kinase and other growth mediating pathways, and we will determine if diet-induced growth in the absence of CCK is dependent on calcineurin, similar to the effect of CCK with a normal diet. (3) We will determine the mechanism of calcineurin in induction of pancreatic protein synthesis and growth. Whether activated calcineurin is sufficient to induce growth and protein synthesis will be determined. We will also determine whether calcincunn-induced gene regulation is involved in the growth response. These studies will be carried out in normal mice fed different diets or gavage-fed trypsin inhibitor or amino acids. They will also make use of a mutant mouse line with CCK-deleted and involve the construction of a transgenic mouse line with constitutively active calcineurin targeted to the pancreas. Studies will be carried out both in vivo and in isolated pancreatic acini. Immunosuppressants such as cyclosponn A and FK506 will be used to inhibit calcineurin and rapamycin to inhibit mTOR. This work, in addition to understanding normal function may assist in designing diets to maximally stimulate pancreatic growth to counteract pancreatic insufficiency.
Funding Period: 2002-08-21 - 2008-11-30
more information: NIH RePORT

Top Publications

  1. ncbi Molecular mechanisms of pancreatic dysfunction induced by protein malnutrition
    Stephen J Crozier
    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109 5622, USA
    Gastroenterology 137:1093-101, 1101.e1-3. 2009
  2. ncbi Early activation of endoplasmic reticulum stress is associated with arginine-induced acute pancreatitis
    Constanze H Kubisch
    Department of Cancer Biology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77230-1429, USA
    Am J Physiol Gastrointest Liver Physiol 291:G238-45. 2006
  3. ncbi Activation of the mTOR signalling pathway is required for pancreatic growth in protease-inhibitor-fed mice
    Stephen J Crozier
    Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA
    J Physiol 573:775-86. 2006
  4. ncbi Calcineurin-dependent and calcineurin-independent signal transduction pathways activated as part of pancreatic growth
    Mitsuo Tashiro
    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-0622, USA
    Pancreas 32:314-20. 2006
  5. ncbi Leucine activates pancreatic translational machinery in rats and mice through mTOR independently of CCK and insulin
    Maria Dolors Sans
    Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
    J Nutr 136:1792-9. 2006
  6. ncbi Induction of early response genes in trypsin inhibitor-induced pancreatic growth
    Lili Guo
    Dept of Molecular and Integrative Physiology, Univ of Michigan Medical School, Ann Arbor, MI 48109 0622, USA
    Am J Physiol Gastrointest Liver Physiol 292:G667-77. 2007
  7. ncbi Cholecystokinin activates pancreatic calcineurin-NFAT signaling in vitro and in vivo
    Grzegorz T Gurda
    Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI 48109 0622, USA
    Mol Biol Cell 19:198-206. 2008
  8. ncbi CCK-induced pancreatic growth is not limited by mitogenic capacity in mice
    Stephen J Crozier
    Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA
    Am J Physiol Gastrointest Liver Physiol 294:G1148-57. 2008

Scientific Experts

  • Stephen J Crozier
  • Grzegorz T Gurda
  • Maria Dolors Sans
  • John A Williams
  • Lili Guo
  • Mitsuo Tashiro
  • Stephen A Ernst
  • Constanze H Kubisch
  • Sae-Hong Lee
  • Sae Hong Lee
  • Thiruvengadam Arumugam
  • Andrzej Dabrowski
  • Craig D Logsdon
  • Scot R Kimball
  • Nancy L Vogel

Detail Information

Publications8

  1. ncbi Molecular mechanisms of pancreatic dysfunction induced by protein malnutrition
    Stephen J Crozier
    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109 5622, USA
    Gastroenterology 137:1093-101, 1101.e1-3. 2009
    ..The purpose of this study was to elucidate the role of mTOR in protein deficiency-induced pancreatic dysfunction...
  2. ncbi Early activation of endoplasmic reticulum stress is associated with arginine-induced acute pancreatitis
    Constanze H Kubisch
    Department of Cancer Biology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77230-1429, USA
    Am J Physiol Gastrointest Liver Physiol 291:G238-45. 2006
    ..These results indicate that ER stress is an important early acinar cell event that likely contributes to the development of acute pancreatitis in the arginine model...
  3. ncbi Activation of the mTOR signalling pathway is required for pancreatic growth in protease-inhibitor-fed mice
    Stephen J Crozier
    Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA
    J Physiol 573:775-86. 2006
    ..We conclude that the mTOR signalling pathway is required for CCK-induced cell division and pancreatic growth...
  4. ncbi Calcineurin-dependent and calcineurin-independent signal transduction pathways activated as part of pancreatic growth
    Mitsuo Tashiro
    Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-0622, USA
    Pancreas 32:314-20. 2006
    ..CONCLUSIONS: The pancreatic growth response is accompanied by activation of a number of signaling pathways regulating transcription and translation, some of which are dependent on and some independent of calcineurin...
  5. ncbi Leucine activates pancreatic translational machinery in rats and mice through mTOR independently of CCK and insulin
    Maria Dolors Sans
    Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
    J Nutr 136:1792-9. 2006
    ..We conclude that leucine may participate, as a signal as well as a substrate, in activating the translational machinery in pancreatic acinar cells independently of hormonal effects and that this action is through the mTOR pathway...
  6. ncbi Induction of early response genes in trypsin inhibitor-induced pancreatic growth
    Lili Guo
    Dept of Molecular and Integrative Physiology, Univ of Michigan Medical School, Ann Arbor, MI 48109 0622, USA
    Am J Physiol Gastrointest Liver Physiol 292:G667-77. 2007
    ..These results indicate that camostat feeding induces a spectrum of early response gene expression and AP-1 DNA binding and that these effects are mainly CCK dependent...
  7. ncbi Cholecystokinin activates pancreatic calcineurin-NFAT signaling in vitro and in vivo
    Grzegorz T Gurda
    Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI 48109 0622, USA
    Mol Biol Cell 19:198-206. 2008
    ..The changes also required calcineurin, as they were blocked by FK506. We conclude that CCK activates NFATs in a calcineurin-dependent manner, both in vitro and in vivo...
  8. ncbi CCK-induced pancreatic growth is not limited by mitogenic capacity in mice
    Stephen J Crozier
    Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI 48109, USA
    Am J Physiol Gastrointest Liver Physiol 294:G1148-57. 2008
    ..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...