Chronic Treatment with Prednisolone Represses the Circadian Oscillation of Clock Gene Expression in Mouse Peripheral Tissues

Abstract

Although altered homeostatic regulation, including disturbance of 24-h rhythms, is often observed in the patients undergoing glucocorticoid therapy, the mechanisms underlying the disturbance remains poorly understood. We report here that chronic treatment with a synthetic glucocorticoid, prednisolone (PSL), can cause alteration of circadian clock function at molecular level. Treatment of cultured hepatic cells (HepG2) with PSL induced expression of Period1 (Per1), and the PSL treatment also attenuated the serum-induced oscillations in the expression of Period2 (Per2), Rev-erbalpha, and Bmal1 mRNA in HepG2 cells. Because the attenuation of clock gene oscillations was blocked by pretreating the cells with a Per1 antisense phosphothioate oligodeoxynucleotide, the extensive expression of Per1 induced by PSL may have resulted in the reduced amplitude of other clock gene oscillations. Continuous administration of PSL into mice constitutively increased the Per1 mRNA levels in liver and skeletal muscle, which seems to attenuate the oscillation in the expressions of Per2, Rev-erbalpha, and Bmal1. However, a single daily administration of PSL at the time of day corresponding to acrophase of endogenous glucocorticoid levels had little effect on the rhythmic expression of clock genes. These results suggest a possible pharmacological action by PSL on the core circadian oscillation mechanism and indicate the possibility that the alteration of clock function induced by PSL can be avoided by optimizing the dosing schedule.

Adrenal peripheral clock controls the autonomous circadian rhythm of glucocorticoid by causing rhythmic steroid production

“…In this regard, it is of interest that adrenal gland-specific ablation of the molecular clock could cause abnormalities in behavioral rhythm under DD cycles; the MC2R-AS-BMAL1 TG mice clearly displayed dampened amplitude of their behavioral rhythm in terms of day-night differences in homecage activities. It is plausible that the dampened plasma CS rhythm was responsible for the changes, because it has been demonstrated that flattened GC profiles could attenuate circadian locomotor activities (39,40). Because the body temperature is not significantly affected in our TG mice, the behavioral alterations are likely due to a selective effect of cyclic GC on brain functions dealing with the expression of periodic locomotor behaviors, such as coordinating motor functions or maintaining sleep-wake cycles (41).…”

“…5D). In connection with such selectivity, it should be noted that the expression of clock genes can be differentially regulated by GC signaling; Per1 expression can be directly modulated via a distal GC-responsive promoter element (39,42). Therefore, it is likely that the reduced circulating CS found in the TG mice is responsible for the alteration of cyclic accumulation of Per1 in peripheral organs as well as the dampened behavioral rhythm.…”

Assessment of circadian function in fibroblasts of patients with bipolar disorder

“…For example, increased expression level of Per1 resulted in reduced amplitude of oscillations in the expression of Per2, RevErba and Bmal1. 96 Disruption of prokineticin 2, a clockcontrolled gene indicated as a candidate SCN clock output signal, led to reduced rhythmicity for a variety of physiological and behavioral parameters. 97 Likewise, reduction in the mRNA level of DEC2 and DBP may result in the dysregulation of their downstream target genes, which may contribute to the risk for bipolar disorder.…”

Characterization of the Core Mammalian Clock Component, NPAS2, as a REV-ERBα/RORα Target Gene

“…The expression of arrays of genes is a function of the molecular clock in the liver and regulate functions, including carbohydrate, fatty acid, cholesterol and bile acid metabolism. HepG2 hepatocellular carcinoma cells have been used as a model to study circadian rhythms in the liver, including the function of CLOCK and BMAL1 as well as the circadian expression of a wide number of genes, including a number of cytochrome p450s (12)(13)(14)(15)(16)(17)(18)(19).…”