RESEARCH ARTICLE Palmitate Inhibits SIRT1-Dependent BMAL1/ CLOCK Interaction and Disrupts Circadian Gene

Elevated levels of serum saturated fatty acid palmitate have been shown to promote insulin resistance, increase cellular ROS production, and trigger cell apoptosis in hepatocytes dur-ing the development of obesity. However, it remains unclear whether palmitate directly im-pacts the circadian clock in hepatocytes, which coordinates nutritional inputs and hormonal signaling with downstreammetabolic outputs. Here we presented evidence that the molecu-lar clock is a novel target of palmitate in hepatocytes. Palmitate exposure at low dose inhib-its the molecular clock activity and suppresses the cyclic expression of circadian targets including Dbp, Nr1d1 and Per2 in hepatocytes. Palmitate treatment does not seem to alter localization or reduce protein expression of BMAL1 and CLOCK, the two core components of the molecular clock in hepatocytes. Instead, palmitate destabilizes the protein-protein in-teraction between BMAL1-CLOCK in a dose and time-dependent manner. Furthermore, we showed that SIRT1 activators could reverse the inhibitory action of palmitate on BMAL1-CLOCK interaction and the clock gene expression, whereas inhibitors of NAD synthesis mimic the palmitate effects on the clock function. In summary, our findings demonstrated that palmitate inhibits the clock function by suppressing SIRT1 function in hepatocytes