Cholestatic ABCB4-deficient mice reveal depression/anxiety-like behavior.

Aims: Depression is commonly associated with chronic liver disease; however, its causality remains largely unknown (Lee et al. Psychosomatics 2013;54:52 – 9). Quantitative phenotypes are linked to psychiatric disorders, thus genetic studies in mice might help to identify modifier genes that influence behavior. Our aim now was to characterize the behavioral phenotype in the ABCB4-deficient (Abcb4–/– ) mouse, a well-established model for chronic cholestatic liver disease.   Methods: We used the Open Field (OF) test, which evaluates spontaneous exploratory drive, reactivity to novelty and emotionality. Specifically, time courses of distance travelled, including speed of movement and time spent in the center, and rearing frequencies were noted in 5-min-intervals. Additionally, we assessed sensorimotor gating by Prepulse Inhibition (PPI) one week after OF at different intensities. The tests were carried out with 18 Abcb4–/– mice and 20 BALB/cJ wild-type controls, aged 10 to 13 weeks.   Results: OF revealed significant genotype effects (p < 0.001) with consistently decreased locomotor activity characterized by reduced speed of movement and increased avoidance of the peripheral and central zones in Abcb4–/– mice. The time course of unconditioned behavior of Abcb4–/– mice in the OF revealed a significant genotype effect on the curve shape of the measured parameters. Furthermore, we detected a significant decrease in rearing activity for Abcb4–/– mice as compared to controls (total frequency 47.8 ± 8.4 vs. 99.0 ± 8.6 [events], p < 0.001). Assessment of PPI revealed a deficit at 69 dB intensity in female Abcb4–/– mice only.   Conclusions: Abcb4–/– mice show greater anxiety behavior and reduced exploratory activity compared to wild-type controls. However, given that ABCB4 is almost exclusively expressed in liver but not in brain, the induced locomotor behavioral alterations are most likely secondary, e.g. caused by neurochemical changes associated with the significantly reduced serum vitamin D levels recently described by us in Abcb4–/– mice. Of note, this model resembles the link between chronic liver diseases and increased stress susceptibility observed in humans. &nbsp

The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis.

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.-Hochrath, K., Krawczyk, M., Goebel, R., Langhirt, M., Rathkolb, B., Micklich, K., Rozman, J., Horsch, M., Beckers, J., Klingenspor, M., Fuchs, H., Gailus-Durner, V., Wolf, E., Acalovschi, M., Volmer, D. A., Hrabě de Angelis, M., Lammert, F. The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis

Modeling hepatic osteodystrophy in Abcb4 deficient mice.

Hepatic osteodystrophy (HOD) denotes the alterations in bone morphology and metabolism frequently observed in patients with chronic liver diseases, in particular in case of cholestatic conditions. The molecular mechanisms underlying HOD are only partially understood. In the present study, we characterized the bone phenotypes of the ATP-binding cassette transporter B4 knockout mouse (Abcb4(-/-)), a well-established mouse model of chronic cholestatic liver disease, with the aim of identifying and characterizing a mouse model for HOD. Furthermore, we investigated the influence of vitamin D on bone quality in this model. The bone morphology analyses revealed reduced bone mineral contents as well as changes in trabecular bone architecture and decreased cortical bone densities in Abcb4(-/-) mice with severe liver fibrosis. We observed dysregulation of genes involved in bone remodeling (osteoprotegerin, osteocalcin, osteopontin) and vitamin D metabolism (7-dehydrocholesterol reductase, Gc-globulin, Cyp2r1, Cyp27a1) as well as alterations in calcium and vitamin D homeostasis. In addition, serum RANKL and TGF-β levels were increased in Abcb4(-/-) mice. Vitamin D dietary intervention was only partially able to restore the bone phenotypes of Abcb4(-/-) animals. We conclude that the Abcb4(-/-) mouse provides an experimental framework and a preclinical model to gain further insights into the molecular pathobiology of HOD and to study the systemic effects of therapeutic interventions. Bone 2013 Aug; 55(2):501-1