RESUMEN
The hepatic phosphatidylcholine (PC) transporter ATP-binding cassette (ABC) B4 flops PC from hepatocytes into bile, and its dysfunction causes chronic cholestasis and fibrosis. Because a nuclear receptor-dependent PC pathway has been determined to exert antidiabetic effects, we now analyzed the role of ABCB4 in glucose metabolism. We bred congenic Abcb4-knockout (Abcb4(-/-)) mice on the fibrosis-susceptible BALB/cJ background. Knockout mice and wild-type controls were phenotyped by measuring plasma glucose concentrations, intraperitoneal glucose tolerance, hepatic RNA expression profiles, and liver histology. In addition, 4 procholestatic ABCB4 gene variants were correlated with blood glucose levels in 682 individuals from 2 independent European cohorts. Systemic glucose levels differ significantly between Abcb4(-/-) mice and wild-type controls, and knockout mice display improved glucose tolerance with significantly lower area under the curve values on intraperitoneal glucose challenge. Of note, hepatic expression of the antidiabetic nuclear receptor 5A2 (LRH-1) is induced consistently in Abcb4(-/-) mice, and its specific rare PC ligands are detected in liver by mass spectrometry imaging. In humans, serum glucose levels are associated significantly with the common ABCB4 variant c.711A>T. In summary, ABCB4 might play a critical role in glucose homeostasis in mice and humans. We speculate that the effects could be mediated via LRH-1-dependent PC pathways.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Glucemia/metabolismo , Homeostasis , Hígado/metabolismo , Fosfatidilcolinas/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Células Cultivadas , Estudios de Cohortes , Femenino , Cálculos Biliares/sangre , Cálculos Biliares/genética , Cálculos Biliares/metabolismo , Perfilación de la Expresión Génica , Humanos , Hígado/patología , Masculino , Ratones , Ratones Congénicos , Ratones Endogámicos BALB C , Ratones Noqueados , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Adulto Joven , Miembro 4 de la Subfamilia B de Casete de Unión a ATPRESUMEN
Barrett's adenocarcinoma currently shows the highest increase in the incidence of all malignant tumors. Reliable molecular markers to identify Barrett's patients at risk are still missing. Our own results demonstrate that the expression of CD44v6 correlates with the development of dysplasia in colorectal neoplasms. Therefore, we examined the expression of CD44 variants v5 and v6 in normal esophageal mucosa, non-dysplastic Barrett's mucosa, and Barrett's carcinoma. mRNA from biopsy specimens of patients with Barrett's esophagus (n = 19) or Barrett's carcinoma (n = 15) and patients without esophageal diseases (controls; n = 9) were extracted and used as templates for cDNA synthesis. CD44 variants were detected by RT-PCR with primers hybridizing with CD44 sequences up- and downstream of variable exons. CD44v6 expression was found in 36 of 56 biopsy specimens (64%) of non-dysplastic Barrett's mucosa, in 100% of squamous epithelium, and in none of the gastric mucosa specimens. Eleven of 15 specimens (73%) of Barrett's carcinoma tested positive for v6 expression. The identification of v5 expression did not give additional information. There was no correlation between CD44v5 or -v6 expression and staging or grading of the tumors. Expression of CD44v5 and -v6 seems to be independent of the development of cancer in Barrett's mucosa.