41 It has been proposed that SIRT1 functions as an enzymatic rheostat of circadian function, transducing signals originated by cellular metabolites to the circadian clock. Furthermore, a specific genetic disruption of the nuclear receptor corepressor 1 (Ncor1) and HADC3, which is activated by Ncor1, leads to aberrant regulation

of clock genes and abnormal circadian behavior.42 In turn, the oscillatory expression pattern of several metabolic genes is disrupted, leading to alternations in energy metabolism. Similarly, our findings show that as a subunit of the chromatin-remodeling complexes, BAF60a alters the local chromatin environment of Bmal1 and G6Pase promoters from a repressive to an active state. Knockdown of BAF60a in the

liver disrupts the rhythmic expression patterns of both click here clock and metabolic genes. Our findings extend the current recognition of the epigenetic regulation of circadian and metabolic physiology and highlight Adriamycin the importance of BAF60a, perhaps plus other SWI/SNF family members, in this process. Last but not least, RORα and RORγ are expressed differently in central and peripheral tissues. RORα mRNA levels are higher than RORγ and are under circadian regulation in the SCN, whereas RORγ is the predominant ROR class protein and shows circadian oscillation in the liver. The peak of the oscillation in each tissue roughly coincides with the peak in Bmal1 mRNA levels.43 This brings concerns to our findings showing that BAF60a coactivates RORα, but not RORγ, to regulate transcriptional activity of the Bmal1 promoter. One possible explanation for this paradox is that, in contrast to the normal liver tissue, HepG2 cells we used in our experiments have more abundant mRNA expression of RORα than that of RORγ (data not shown)

and thus establish some distinct regulative pathways in which RORα plays a dominant role. Second, even though RORγ oscillates robustly and serves as the major regulator of Bmal1 transcription in the liver, the coactivation of RORα with BAF60a may provide a nonredundant complementary mechanism for the regulation of circadian oscillators by RORγ. A growing body of epidemiological and experimental 上海皓元医药股份有限公司 evidence indicates that circadian clock system disruption is detrimental to metabolic homeostasis, yet the precise underlying mechanisms involved remain unknown. In this context, misregulation of key genes of gluconeogenesis, fatty acid β-oxidation, and mitochondrial respiration, as observed in the mice with liver-specific BAF60a knockdown, may constitute one factor contributing to metabolic imbalance in individuals chronically exposed to abnormal circadian cycle conditions, such as shift workers and cabin crews. In conclusion, we have identified that BAF60a, a novel circadian regulator, links clock signals to liver metabolic physiology (Fig. 7). We thank Drs. J. Goldstein and B.