Mice with liver-specific knockdown of BAF60a show abnormalities in the rhythmic expression pattern of clock Ponatinib mw and metabolic genes and in the circulating metabolite profile. Consistently, knockdown of BAF60a impairs the oscillation of clock genes in serum-shocked HepG2 cells. At the molecular level, BAF60a activates Bmal1 and G6Pase transcription by way of the coactivation of retinoid-related orphan receptor alpha (RORα). In addition, BAF60a is present near ROR response elements (RORE) on the proximal Bmal1 and G6Pase promoters and turns the chromatin structure into the active state. Conclusion: Our data suggest a critical role for BAF60a in the coordinated regulation of hepatic circadian clock and energy metabolism

in mammals. (HEPATOLOGY 2011;) Many physiological events in mammals, including locomotor activity, sleep, blood

pressure, circulating hormones, and energy metabolism show diurnal fluctuation.1, 2 These intrinsic biological rhythms are mainly entrained by light-dark (LD) and feeding cycles. The mammalian master clock resides in the hypothalamic suprachiasmatic nucleus (SCN) and drives slave oscillators distributed Stem Cell Compound Library in various peripheral tissues through behavioral and neuroendocrine signals. However, Damiola et al.3 found that peripheral oscillators can be uncoupled and reset from the central pacemaker by restricted feeding. Their findings are supported by the subsequent report showing that restricted feeding entrains the circadian rhythms in peripheral tissues, dominantly in the liver, but leaving SCN rhythms unaffected.4 Also, both food availability and the temporal pattern of feeding determine the repertoire, phase, and amplitude

of the circadian transcriptome in mouse liver.5 All these studies indicate that nutritional signals play a dominant role in the regulation of peripheral clock function. At the molecular level, Clock and Bmal1 are two basic helix-loop-helix transcription factors that activate the transcription of period (Per) and cryptochrome (Cry) genes.6 Per and Cry proteins in turn inhibit their own expression by repressing Clock/Bmal1 activity, forming the critical feedback find more loop within the clock circuitry. In addition, the orphan nuclear receptors of the ROR and Rev-erb families are also implicated in the control of circadian clock function.7, 8 It has been shown that neuroendocrine and metabolic systems are subjected to strong circadian control. Recent transcriptional profiling studies indicate that ≈10% of all genes in the genome display rhythmic expression under constant dark conditions,2, 9 many of which encode enzymes involved in glucose, lipid, amino acids, heme, and mitochondrial oxidative metabolism. In particular, hepatic lipogenesis, gluconeogenesis, heme, and bile acid biosynthesis as well as xenobiotic detoxification are cyclic in rodents and humans.10-13 In contrast, some key regulators in circadian clock have their own metabolic functions.