Functionally, previous study indicated that BAF60a stimulates fatty acid β-oxidation and ameliorates hepatic steatosis in vivo.24 We also found that mice have hypoglycemia when BAF60a is knocked down in the liver. Consistently, overexpression of BAF60a in mouse hepatocytes increase the glucose production rate. The positive effects of BAF60a on glucose levels may due to the induction of gluconeogenic genes such as G6Pase and PEPCK (Fig. 5 and data not shown) by BAF60a and the accelerated rate of gluconeogenic process. These observations
collectively extend our recognition of physiological roles of this factor, whose function is traditionally limited in the regulation of chromatin structure. Future study is required to elucidate the functions find more of BAF60a and other BAF60 proteins, BAF60b and BAF60c, in various metabolic tissues under physiological and pathological status. Similar to the control of the circadian clock on metabolism, food is a very potent synchronizer (zeitgeber) for peripheral clocks. Recent work investigating the respective contributions of feeding and of the circadian clock to hepatic rhythmic Selleck Adriamycin gene expression using clock-deficient mice and the temporally restricted feeding paradigm has shown that oscillations of food-induced transcripts, including those from the gluconeogenic and fatty acid
oxidation pathways, are modulated and consolidated by the clock.37 Reciprocally, the robustness of the clock and its immediate downstream targets is increased by temporally restricted feeding. medchemexpress The expression of BAF60a itself is not altered by food signals,24 but it is a clock target that
modulates the expression of food-driven metabolic genes, such as PEPCK and Cpt1a. In this sense, a principle function of BAF60a may be to temporally modulate the food-entrained daily oscillation of components of specific metabolic pathways. On the other hand, we cannot exclude the possibility that BAF60a mediates food-induced reset of the peripheral clock at the posttranslational levels. The rhythmic recruitments of BAF60a to metabolic gene promoters need to be examined. Circadian function is largely based on a program of finely controlled transcriptional regulation at the genome-wide level. The intrinsic nature of its highly specialized, temporally regulated transcription places the cellular clock as a prominent model for the study of dynamic chromatin remodeling.38, 39 Moreover, based on the tight coupling between circadian rhythms and metabolic regulation,18 clock-controlled chromatin reorganization is likely to reveal specific pathways linking histone modifications to cellular metabolism. For example, the central clock protein Clock has histone acetyltransferase (HAT) enzymatic properties.40 It directs acetylation of histone H3 and its dimerization partner Bmal1 at K537, an event essential for circadian function.