It has been proposed that this unusual use of NAD+ makes these sirtuins sensors of cellular NAD+ levels. Cellular and nuclear NAD+ levels are close enough to the Km of SIRT1 for NAD+ to make this plausible (103). In this view, cellular NAD+ levels would change in response to metabolic fluxes or stresses and cause changes in histone and other nuclear protein acetylation with consequences on gene expression. Conflicts have been noted between this model and early studies on NAD+ levels that showed little response to starvation (92). NAD+ levels do cycle with circadian rhythms (104) and increase with exercise (105). NAD+/NADH ratios decrease in response to elevated glucose levels in C2C12 skeletal muscle cells while in the muscles of fasted mice SIRT1 decreases expression of AMPK targets in control animals and is necessary for their induction after fasting (106). In mouse liver, NAD+ levels are increased by 33% after fasting for 24 h and return to control levels after 24 h after refeeding (107). SIRT1 protein levels were induced after refeeding, showing a second mechanism for SIRT1 activity regulation.
