Hormonal regulation of oligopeptide transporter  Pept-1 in a human intestinal cell line

Thamotharan, Manikkavasagar; Bawani, Shahab Zare; Zhou, Xiaodong; Adibi, Siamak A.

doi:10.1152/ajpcell.1999.276.4.c821

Cited by 146 publications

(93 citation statements)

References 18 publications

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“…It is also unclear how hormonal or neural pathways affect oligopeptide regulation in the developing intestine and kidney. These factors were beyond the scope of the present study, but may be important as suggested previously (11,20,34).…”

mentioning

confidence: 72%

Developmental Expression of PEPT1 and PEPT2 in Rat Small Intestine, Colon, and Kidney

2001

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Mammalian peptide transporters (PEPT1 and PEPT2) play a pivotal role in the absorption of small peptides from the intestine and kidney, respectively, and in the disposition and targeting of peptide or mimetic drugs. However, there are few reports on the molecular basis of their regulation, especially in the young. The aim of this study was to determine the developmental expression of intestinal and renal oligopeptide transporters in rats from embryonic to adult ages. Intestinal segments were collected (i.e. duodenum, jejunum, ileum, and colon) along with whole kidney, and their mRNA and protein levels were measured. Expression levels of PEPT1 were maximal 3-5 d after birth in the duodenum, jejunum, and ileum, and then declined rapidly. Expression was increased transiently at d 24, most notably in the ileum. Adult protein levels were approximately 70% of that observed on d 3-5. Significant PEPT1 expression was observed in colon during the first week of life, but levels were undetectable shortly thereafter through adulthood. PEPT1 and PEPT2 expression is less regulated in rat kidney and more pronounced in older animals. Peptide transporters were also present as early as d 20 of fetal life for all tissues tested. These results are unique in providing the developmental expression of peptide transporter mRNA and protein in distinct regions of the small intestine, colon, and kidney in rat. Our findings suggest that intestinal expression of PEPT1 is induced postpartum, possibly by suckling, and again at the time of weaning, and that the colon may participate in peptide transport early in life. Expression and molecular cloning studies have resulted in the identification of two distinct proton-coupled oligopeptide transporters in rabbit (1-3), rat (4 -6), and human (7, 8) (i.e. PEPT1 as low-affinity carrier, PEPT2 as high-affinity carrier). The proteins range in size from 707 to 729 amino acids in various species, with high homology between species for a given transporter (approximately 80%) and less homology between transporters for a given species (approximately 50%). The gene products, as predicted by hydropathy analysis, contain 12 membrane-spanning domains and a large extracellular loop between transmembrane domains 9 and 10. The encoded proteins have a number of potential N-glycosylation as well as protein kinase recognition sites, which suggests that the transporters may be regulated by reversible phosphorylation. More recently, a third peptide transporter, PHT1, was cloned from rat brain (9). Encoding a protein of 572 amino acids, hydropathy analysis predicts the presence of 12 transmembrane domains. There are also multiple N-glycosylation sites in the hydrophilic extracellular loop of PHT1, along with potential sites for protein kinase C-dependent phosphorylation. PHT1 is novel in that it transports histidine, as well as small peptides, with high affinity and in a proton gradient-dependent manner. Although expressed in the brain and eye, PHT1 is not found in the intestine or kidney and shows little homology to P...

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confidence: 72%

Developmental Expression of PEPT1 and PEPT2 in Rat Small Intestine, Colon, and Kidney

2001

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“…In this regard, the role of insulin in the regulation of a number of intestinal epithelial processes is well established. For example, insulin has been shown to stimulate the function of oligopeptide transporter, Pept-1 (36), to decrease the transepithelial resistance (28), and to abrogate calcium-dependent chloride secretion in T84 intestinal epithelial cells (8). Additionally, previous studies have shown that insulin acutely decreased glucose flux across rat jejunum and ileum (27).…”

Section: G903 High Bile Acid Absorption In Stz-induced Diabetes Mellitusmentioning

confidence: 99%

Ileal apical Na⁺-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin

Annaba

Kumar

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin. Am J Physiol Gastrointest Liver Physiol 299: G898 -G906, 2010. First published July 22, 2010; doi:10.1152/ajpgi.00139.2010.-Increased intestinal bile acid absorption and expansion of the bile acid pool has been implicated in the hypercholesterolemia associated with diabetes mellitus. However, the molecular basis of the increase in bile acid absorption in diabetes mellitus is not fully understood. The ileal apical Na ϩ -dependent bile acid transporter (ASBT) is primarily responsible for active reabsorption of the majority of bile acids. Current studies were designed to investigate the modulation of ASBT function and expression in streptozotocin (STZ)-induced diabetes mellitus in rats and to examine the effect of insulin on rat ASBT promoter by insulin. Diabetes mellitus was induced in Sprague-Dawley rats by intraperitoneal injection of low doses of STZ (20 mg/kg body wt) on five consecutive days. Human insulin (10 U/day) was given to a group of diabetic rats for 3 days before euthanasia. RNA and protein were extracted from mucosa isolated from the small intestine and ASBT expression was assessed by real-time quantitative RT-PCR and Western blotting. Our data showed that ASBT mRNA and protein expression were significantly elevated in diabetic rats. Insulin treatment of diabetic rats reversed the increase in ASBT protein expression to control levels. Consistently, ileal Na ϩ -dependent [ 3 H]taurocholic uptake in isolated intestinal epithelial cells was significantly increased in diabetic rats. In vitro studies utilizing intestinal epithelial Caco-2 cells demonstrated that ASBT expression and promoter activity were significantly decreased by insulin. These studies demonstrated that insulin directly influences ASBT expression and promoter activity and that ASBT function and expression are increased in rats with STZinduced diabetes mellitus. The increase in ASBT expression may contribute to disturbances in cholesterol homeostasis associated with diabetes mellitus. hypercholesterolemia; insulinopenia; enterohepatic circulation DIABETES MELLITUS IS A COMPLEX disorder resulting from insulin imbalance and characterized by dyslipidemia and hypercholesterolemia (18,34

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“…In Caco-2 cells, insulin (65), leptin (15), 1 -and ␣ 2 -adrenergic receptor ligands such as (ϩ)pentazocine (26), and clonidine (9) all were shown to stimulate uptake of dipeptides or ␤-lactams via PEPT1. On the other hand, either exposure to two immunosuppressive agents, tacrolimus and cyclosporin A (44), or exposure to thyroid hormone (5) or long-term basolateral stimulation with EGF inhibited the uptake of dipeptides via PEPT1 in Caco-2 cells (44).…”

Section: Regulation Of Expression Level and Transport Activity Of Pepmentioning

confidence: 99%

An update on renal peptide transporters

Daniel

Rubio‐Aliaga

2003

American Journal of Physiology-Renal Physiology

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Daniel, Hannelore, and Isabel Rubio-Aliaga. An update on renal peptide transporters. Am J Physiol Renal Physiol 284: F885-F892, 2003; 10.1152/ajprenal.00123.2002The brush-border membrane of renal epithelial cells contains PEPT1 and PEPT2 proteins that are rheogenic carriers for short-chain peptides. The carrier proteins display a distinct surface expression pattern along the proximal tubule, suggesting that initially di-and tripeptides, either filtered or released by surface-bound hydrolases from larger oligopeptides, are taken up by the low-affinity but high-capacity PEPT1 transporter and then by PEPT2, which possesses a higher affinity but lower transport capacity. Both carriers transport essentially all possible di-and tripeptides and numerous structurally related drugs. A unique feature of the mammalian peptide transporters is the capability of proton-dependent electrogenic cotransport of all substrates, regardless of their charge, that is achieved by variable coupling in proton movement along with the substrate down the transmembrane potential difference. This review focuses on the postcloning research efforts to understand the molecular physiology of peptide transport processes in renal tubules and summarizes available data on the underlying genes, protein structures, and transporter function as derived from studies in heterologous expression systems. PEPT1; PEPT2; renal physiology; localization; functional analysis RENAL TUBULAR PEPTIDE TRANSPORT activity was originally discovered after intravenous infusion of the resistant dipeptide Gly-Sar in rats that resulted in a high accumulation of the intact dipeptide in renal tissue (1, 3). Studies with renal brush-border membrane vesicles established that renal apical peptide uptake was an electrogenic, proton-dependent uphill transport process for di-and tripeptides and related drugs mediated by two kinetically different systems (for a review, see Ref. 38). The underlying proteins, differing in transport characteristics, now designated as PEPT1 (SLC15A1) and PEPT2 (SLC15A2), have been identified, and the corresponding genes have been cloned from a variety of species (10,24,25,39,41,(52)(53)(54). The transporters have been expressed in various cellular models, and information on structure, transport function, and regulation has been gathered by flux studies and electrophysiological techniques. Expression analysis of transporter mRNA and protein by in situ hybridization and immunohistochemistry has extended our knowledge of tissue distribution, particularly the renal zonation of PEPT1 and PEPT2 surface expression. THE MOLECULAR ENTITIES OF APICAL PEPTIDE TRANSPORTPEPT1 and PEPT2 are polytopic integral membrane proteins with 12 predicted membrane-spanning domains and NH 2 -and COOH-terminal ends facing the cytosol. Transporter architecture and membrane topology have not been studied systematically, and therefore structural information is still mainly based on hydropathic analysis of amino acid sequences. The mammalian PEPT1 proteins comprise 701-710 amino acids, ...

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Hormonal regulation of oligopeptide transporter Pept-1 in a human intestinal cell line

Cited by 146 publications

References 18 publications

Developmental Expression of PEPT1 and PEPT2 in Rat Small Intestine, Colon, and Kidney

Developmental Expression of PEPT1 and PEPT2 in Rat Small Intestine, Colon, and Kidney

Ileal apical Na⁺-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin

An update on renal peptide transporters

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Hormonal regulation of oligopeptide transporter Pept-1 in a human intestinal cell line

Cited by 146 publications

References 18 publications

Developmental Expression of PEPT1 and PEPT2 in Rat Small Intestine, Colon, and Kidney

Developmental Expression of PEPT1 and PEPT2 in Rat Small Intestine, Colon, and Kidney

Ileal apical Na+-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin

An update on renal peptide transporters

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Ileal apical Na⁺-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin