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
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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