Abstract
In a previous study, oral IGF-I at 65 nM increased lactase phlorizin hydrolase (LPH) activity and villus height in piglets, however, the mechanisms were unknown. Herein, the response to a range of doses of IGF-I was investigated and we hypothesized that LPH and villus height would respond to oral IGF-I in a dose-dependent manner. Two 14-d experiments were conducted using cesarean-derived piglets. In experiment 1, piglets (n = 28) were fed formula containing 0, 33, 65, or 131 nmol/L (0, 0.25, 0.5, or 1.0 mg/L) recombinant human IGF-I. In experiment 2, 5′-bromodeoxyuridine was administered to piglets fed formula alone (n = 4) or containing 131 nmol/L IGF-I (n = 4). IGF-I did not affect body weight gain or intestinal weight or length. Jejunal villus height and LPH activity were significantly greater in piglets fed 131 nmol IGF-I/L than control piglets. Villus height and lactase activity in piglets fed the 33 and 65 nmol/L IGF-I doses were similar and intermediate between control and 131 nmol IGF-I/L. Jejunal mRNA expression and LPH polypeptide abundance were investigated in piglets receiving 0 or 131 nmol/L IGF-I. Steady state LPH mRNA abundance was significantly higher (p < 0.05) in IGF-I-treated piglets. The relative abundance of proLPHh was not significantly increased (p = 0.06) by IGF-I treatment. Mucosal DNA content and DNA synthesis were greater in piglets receiving 131 nmol IGF-I/L than control, however, enterocyte migration and mucosal protein content were unaffected. Thus, oral IGF-I increased jejunal LPH activity and LPH mRNA abundance and stimulated intestinal cell hyperplasia in normal piglets.
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Abbreviations
- AP-1:
-
activator protein-1
- BrdU:
-
5′-bromodeoxyuridine
- C/EBP:
-
CCAAT/enhancer binding protein
- EF1-α:
-
elongation factor 1-α
- FLE:
-
foremost labeled enterocyte
- HNF-1:
-
hepatocyte nuclear factor-1
- LPH:
-
lactase phlorizin hydrolase
- BB LPH:
-
brush border lactase phlorizin hydrolase
- proLPHh:
-
high mannose lactase phlorizin hydrolase precursor
- proLPHc:
-
complex glycosylated lactase phlorizin hydrolase precursor
- MAPK:
-
mitogen activated protein kinase
- NHS:
-
normal horse serum
- PI 3-kinase:
-
phosphatidylinositol 3-kinase
References
Donovan SM, Hintz RL, Rosenfeld RG 1991 Insulin-like growth factors I and II and their binding proteins in human milk: effect of heat treatment on IGF and IGF binding protein stability. J Pediatr Gastroenterol Nutr 13: 242–253
Morgan CH, Coutts AGP, McFadyen MC, King TP, Kelly D 1996 Characterization of IGF-I receptors in porcine small intestine during postnatal development. J Nutr Biochem 7: 339–347
Donovan SM, Odle J 1994 Growth factors in milk as mediators of infant development. Annu Rev Nutr 14: 147–167
Xu R-J, Mellor DJ, Birtles MJ, Breier BH, Guckman PD 1994 Effects of oral IGF-I or IGF-II on digestive organ growth in newborn piglets. Biol Neonate 66: 280–287
Burrin DG, Wester TJ, Davis TA, Amick S, Heath JP 1996 Orally administered insulin-like growth factor-I increases intestinal mucosal growth in formula-fed neonatal pigs. Am J Physiol 270: R1085
Houle VM, Schroeder EA, Odle J, Donovan SM 1997 Small intestinal disaccharidase activity and ileal villus height is increased in piglets consuming formula containing recombinant human insulin-like growth factor-I. Pediatr Res 24: 78–86
Donovan SM, McNeil LK, Jiménez-Flores R, Odle J 1994 Insulin-like growth factors and IGF binding proteins in porcine serum and milk throughout lactation. Pediatr Res 36: 159–168
Dudley MA, Burrin DG, Quaroni A, Rosenberger J, Cook G, Nichols BL, Reeds PJ 1996 In vivo lactase phlorizin hydrolase turnover in water-fed and colostrum-fed newborn piglets. Biochem J 320: 735–743
Dudley MA, Wykes L, Dudley AW, Fiorotto M, Burrin DG, Rosenberger J, Jahoor F, Reeds PJ 1997 Lactase phlorizin hydrolase synthesis is decreased in protein-malnourished pigs. J Nutr 127: 687–693
Institute of Laboratory Animal Research, National Research Council 1996 Guide for the Care and Use of Laboratory Animals, 7th Ed. National Academy of Sciences Press, Washington, DC, pp 1–124
Tavakkol A, Simmen FA, Simmen RCM 1988 Porcine insulin-like growth factor-I (pIGF-I): complementary deoxyribonucleic acid cloning and uterine expression of messenger ribonucleic acid encoding evolutionarily conserved IGF-I peptides. Mol Endocrinol 2: 674–681
Labarca C, Paigen K 1980 A simple, rapid and sensitive DNA assay procedure. Anal Biochem 102: 344–352
Peterson GL 1977 A simplification of the protein assay method of Lowry et al. Anal Biochem 83: 346–356
Avivi C, Rosen O, Goldstein RS 1994 New chromogens for alkaline phosphatase histochemistry: salmon and magenta phosphate are useful for single- and double-label immunohistochemistry. J Histochem Cytochem 42: 551–554
Wahl GM, Stern M, Stark GR 1979 Efficient transfer of large DNA fragments from agarose gels to diazobenzyloxymethyl-paper and rapid hybridization using dextran sulfate. Proc Natl Acad Sci U S A 76: 3683–3687
Mantei N, Villa M, Enzler T, Wacker H, Boll W, James P, Hunziker W, Semenza G 1988 Complete primary structure of human and rabbit lactase-phlorizin hydrolase: implications for biosynthesis, membrane anchoring and evolution of the enzyme. EMBO J 7: 2705–2713
Chandrasena G, Sunitha I, Lau C, Nanthakumar NN, Henning SJ 1992 Expression of sucrase-isomaltase mRNA along the villus-crypt axis in the rat small intestine. Cell Mol Biol 38: 243–254
Philipps AF, Anderson GG, Dvorak B, Williams CS, Lake M, LeBouton AV, Koldovsky O 1995 Fate of insulin-like growth factors I and II administered orogastrically to suckling rats. Pediatr Res 37: 586–592
Donovan SM, Chao JC-J, Zijilstra RT, Odle J 1997 Orally administered iodinated recombinant human insulin-like growth factor-I (125I-rhIGF-I) is poorly absorbed by the neonatal piglet. J Pediatr Gastroenterol Nutr 24: 174–182
Philipps AF, Anderson GG, Dvorak B, Williams CS, Lake M, LeBouton AV, Koldovsky O 1997 Growth of artificially-fed infant rats: effect of supplementation with insulin-like growth factor-I. Am J Physiol 272: R1532
Ma L, Xu RJ 1997 Oral insulin-like growth factor-I stimulates intestinal enzyme maturation in newborn rats. Life Sci 61: 51–58
Young GP, Taranto TM, Jonas HA, Cox AJ, Hogg A, Werther GA 1990 Insulin-like growth factors and the developing and mature rat small intestine: receptors and biological actions. Digestion 46: 240–252
Xian CJ, Shoubridge CA, Read LC 1995 Degradation of IGF-I in the adult rat gastrointestinal tract is limited by a specific antiserum or the dietary protein casein. J Endocrinol 146: 215–225
Park Y-K, Monaco MH, Donovan SM 1999 Enteral insulin-like growth factor-I augments intestinal disaccharidase activity in piglets receiving total parenteral nutrition. J Pediatr Gastroenterol Nutr 29: 198–206
Carey HV 1997 How to make the gut grow. Gastroenterol 112: 1420–1422
Goda T, Yasutake H, Suzuki Y, Takase S, Koldovsky O 1995 Diet-induced changes in gene expression of lactase in rat jejunum. Am J Physiol 268: G1066
Van Beers EH, Buller HA, Grand RJ, Einerhand AWC, Dekker J 1995 Intestinal brush border glycohydrolases: structure, function, and development. Crit Rev Biochem Mol Biol 30: 197–262
Boukamel R, Freund JN 1992 The rat LPH gene 5′ region: comparative structure with the human gene. DNA Seq 2: 119–121
Spodsberg N, Troelsen JT, Carlsson P, Enerback S, Sjostrom H, Noren O 1999 Transcriptional regulation of pig lactase-phlorizin hydrolase: involvement of HNF-1 and FREACS. Gastroenterology 116: 8423–8454
Montgomery RK, Rings EH, Thompson JF, Schuijt CC, Aras KM, Wielenga VJ, Kothe MJ, Buller HA, Grand RJ 1997 Increased C/EBP in fetal rat small intestine precedes initiation of differentiation marker mRNA synthesis. Am J Physiol 272: G534
Guerra C, Benito M, Fernandez M 1994 IGF-I induces the uncoupling protein gene expression in fetal rat brown adipocyte primary cultures: role of C/EBP transcription factors. Biochem Biophys Res Commun 201: 813–819
Teruel T, Valverde AM, Navarro P, Benito M, Lorenzo M 1998 Inhibition of PI 3-kinase and RAS blocks IGF-I and insulin-induced uncoupling protein 1 gene expression in brown adipocytes. J Cell Physiol 176: 99–109
Minegishi T, Hirakawas T, Kishi H, Abe K, Abe Y, Mizutani T, Miyamoto K 2000 A role of insulin-like growth factor I for follicle-stimulating hormone receptor expression in rat granulosa cells. Biol Reprod 62: 325–333
LaVoie HA, Garmey J, Day RN, Veldhuis JD 1999 Concerted regulation of low density lipoprotein receptor gene expression by follicle-stimulating hormone and insulin-like growth factor I in porcine granulosa cells: promoter activation, messenger ribonucleic acid stability, and sterol feedback. Endocrinology 140: 178–186
Jehle PM, Fussgaenger RD, Blum WF, Angelus NK, Hoeflich A, Wolf E, Jungwirth RJ 1999 Differential autocrine regulation of intestine epithelial cell proliferation and differentiation by insulin-like growth factor (IGF) system components. Horm Metab Res 31: 97–102
Xu R-J, Mellor DJ, Birtles MJ, Reynolds GW, Simpson HV, Breier BH, Gluckman PD 1996 Morphological changes in the oesophagus of newborn pigs: effects of age, diet and oral insulin-like growth factor I (IGF-I) or IGF-II. Reprod Fertil Dev 8: 903–909
Moon HW 1971 Epithelial cell migration in the alimentary mucosa of the suckling pig. Proc Soc Exp Biol Med 137: 151–154
Potten CS, Chwalinski S, Swindell R, Palmer M 1982 The spatial organization of the hierarchical proliferative cells of the crypts of the small intestine into clusters of synchronized cells. Cell Tissue Kinet 15: 351–370
Peterson CA, Carey HV, Hinton PL, Lo HC, Ney DM 1997 GH elevates serum IGF-I levels but does not alter mucosal atrophy in parenterally fed rats. Am J Physiol 272: G1100
Stewart CE, Rotwein P 1996 Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors. Physiol Rev 76: 1005–1026
Lund PK 1998 Molecular basis of intestinal adaptation the role of the insulin-like growth factor system. Ann N Y Acad Sci 859: 18–36
Raab S, Leiser R, Kemmer H, Claus R 1998 Effects of energy and purines in the diet on proliferation differentiation and apoptosis in the small intestine of the pig. Metabolism 47: 1105–1111
Acknowledgements
The authors thank Dr. Clifford Shipley of the University of Illinois School of Veterinary Medicine for performing cesarean sections, Judy Rosenberger (CNRC, Houston, TX, U.S.A.) for assistance with LPH analyses, and the Carle Hospital Clinic Laboratory (Urbana, IL, U.S.A.) for sectioning of intestinal samples.
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Funded by a grant from the National Institutes of Health (HD29264).
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Houle, V., Park, Y., Laswell, S. et al. Investigation of Three Doses of Oral Insulin-like Growth Factor-I on Jejunal Lactase Phlorizin Hydrolase Activity and Gene Expression and Enterocyte Proliferation and Migration in Piglets. Pediatr Res 48, 497–503 (2000). https://doi.org/10.1203/00006450-200010000-00013
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DOI: https://doi.org/10.1203/00006450-200010000-00013
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