Molecular Mechanisms Of Biofilm And Energy Metabolism In The Integration Of Liver Fibrous Resin Complex Subunits BAF60a

Many physiological events in mammals, including locomotor activity, sleep-wake, blood pressure, circulating hormones and energy metabolism show diurnal fluctuation. These intrinsic biological rhythms are mainly entrained by light-dark (LD) and feeding cycles. The mammalian master clock resides in the hypothalamic suprachiasmatic nucleus (suprachiasmatic nucleus, SCN) and drives slave oscillators distributed in various peripheral tissues through behavioral and neuroendocrine signals. However, peripheral oscillators can be uncoupled and reset from the central pacemaker by restricted feeding, indicating that nutritional signals play a dominant role in the regulation of peripheral clock function.It has been shown that neuroendocrine and metabolic systems are subjected to strong circadian control. Recent transcriptional profiling studies indicate that approximately 10% of all genes in the genome display rhythmic expression throughout the LD cycles, 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. In contrasting, some key regulators in circadian clock have their own metabolic functions.Till now, the molecular mechanism for coordinate integration of the circadian clock and energy metabolism has been extensively studied. Peroxisome proliferator-activated receptor (PPAR)-γcoactivator-1α(PGC-1α), an important metabolic coactivator, modulates circadian clocks and energy metabolism simultaneously through coactivating RORs (retinoic acid-related orphan receptor a/y).Recently, Li and her colleagues identified BAF60a as a partner of PGC-la to regulate hepatic lipid metabolism in a genome-wide coactivation analysis. BAF60a is a subunit of the SWI/SNF chromatin-remodeling complexes which regulate nucleosome and chromatin structure through ATP hydrolysis. Interestingly, BAF60a expression shows robust diurnal oscillation in the liver. Based on these observations, we hypothesized that B AF60a may play a potential role in the integration of circadian clock and energy metabolism and carried out the current study to test our hypothesis.Our results showed that BAF60a was rhythmically expressed in the liver of mice. Mice with liver-specific knockdown of BAF60a showed abnormalities in the rhythmic expression pattern of clock and metabolic genes and in the circulating metabolite profile. Consistently, Knockdown of BAF60a impaired the oscillation of clock genes in serum-shocked HepG2 cells. At the molecular level, BAF60a activated Bmall and G6Pase transcription via the coactivation of RORa. In addition, BAF60a was present near RORE on the proximal Bmall and G6Pase promoters and turned the chromatin structure into active state. Finally, we found the rhythmic expression pattern of BAF60a mRNA was disrupted in circadian gene mutant mice. Our data revealed a critical role for BAF60a in the coordinate regulation of hepatic circadian clock and energy metabolism in mammals.