Mice without the Regulator Gene Rsc1A1 Exhibit Increased Na+-d -Glucose Cotransport in Small Intestine and Develop Obesity
| Autor: | Reinhart Kluge, Frank Stümpel, Marina Akimjanova, Klaus-Peter Knobeloch, Ivan Horak, Katharina Baumgarten, Hermann Koepsell, Hans-Georg Joost, Christina Osswald, Valentin Gorboulev |
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| Rok vydání: | 2005 |
| Předmět: |
Leptin
Male Time Factors Transcription Genetic Polymerase Chain Reaction Mice Intestine Small Mammalian Genetic Models with Minimal or Complex Phenotypes Insulin Sodium-Glucose Transporter 1 Cloning Molecular Intestinal Mucosa RNA Processing Post-Transcriptional Epithelial polarity Glucose Transporter Type 2 Mice Knockout 2. Zero hunger 0303 health sciences Membrane Glycoproteins digestive oral and skin physiology 030302 biochemistry & molecular biology Up-Regulation Cell biology Blotting Southern Cholesterol Phenotype medicine.anatomical_structure Biochemistry Female Casein kinase 2 Monosaccharide Transport Proteins Blotting Western Enzyme-Linked Immunosorbent Assay Biology Transfection 03 medical and health sciences Sex Factors medicine Animals Obesity Molecular Biology Protein kinase C 030304 developmental biology Models Genetic Sodium Glucose transporter Biological Transport Cell Biology Blotting Northern Introns Small intestine Glucose Microscopy Fluorescence biology.protein GLUT2 Cotransporter |
| Zdroj: | Molecular and cellular biology, 25(1): 78-87 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.25.1.78-87.2005 |
| Popis: | Glucose absorption in the small intestine is essential for energy supply through carbohydrates. It is mediated by two transporters in the enterocytes, the sodium-dependent d-glucose cotransporter SGLT1 in the brush border membrane and the sodium-independent glucose transporter GLUT2 in the basolateral membrane (11). Na+-d-glucose cotransporter expression and activity in the small intestine exhibits circadian periodicity and is increased following a carbohydrate-rich diet (5, 27). The regulation of SGLT1 can be mediated by adrenergic innervation, insulin, glucagon 37, glucagon-like peptide 2, and cholecystokinin (2, 13, 14, 29, 30). SGLT1 may be regulated by changes in transcription (23, 35), mRNA stability (21), endocytosis (12), and transport activity within the plasma membrane (34). Previously, several related 67-kDa polypeptides from humans, pigs, and rabbits, termed RS1, which show about 70% amino acid identity and are involved in the regulation of SGLT1, were cloned (17, 18, 26, 36). The RS1 polypeptides are encoded by intronless single copy genes (RSC1A1 on chromosome 1p36.1 in humans). These genes are expressed in many cell types, including small intestinal enterocytes and renal proximal tubular cells (18, 26, 36). RS1 contains consensus sequences for protein kinase C and casein kinase II and a ubiquitin-associated domain that is conserved between different species (33). The RS1 protein is localized intracellularly and associated with the plasma membrane (33). Coexpression experiments with Xenopus laevis oocytes showed that human RS1 (hRS1) is involved in posttranscriptional down-regulation of hSGLT1 (18, 26, 36, 37). The down-regulation of hSGLT1 by hRS1 was dynamin dependent and increased by activation of protein kinase C (PKC) (37). Remarkably, RS1 also inhibited the transcription of SGLT1 (17). In the renal epithelial cell line LLC-PK1, where endogenous SGLT1 is up-regulated after confluence, the transcription of SGLT1 was increased 10-fold when the concentration of endogenous RS1 was reduced via an antisense strategy (17). To elucidate the biological significance of RS1 in vivo, we generated a knockout mouse lacking the RS1 protein via homologous recombination in embryonic stem cells. RS1−/− mice develop obesity with increased expression of SGLT1 and enhanced glucose absorption in the small intestine. |
| Databáze: | OpenAIRE |
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