In mammals, many aspects of metabolism are under circadian control. At least in part, this regulation is achieved by core-clock or clock-controlled
transcription factors whose abundance and/or activity oscillate during the day. The clock-controlled
proline- and
acidic amino acid-rich domain basic leucine zipper
proteins D-site-binding
protein, thyrotroph embryonic factor, and hepatic
leukemia factor have previously been shown to participate in the circadian control of
xenobiotic detoxification in liver and other peripheral organs. Here we present genetic and biochemical evidence that the three
proline- and
acidic amino acid-rich basic leucine zipper
proteins also play a key role in circadian lipid metabolism by influencing the rhythmic expression and activity of the
nuclear receptor peroxisome proliferator-activated receptor α (PPARα). Our results suggest that, in liver, D-site-binding
protein, hepatic
leukemia factor, and thyrotroph embryonic factor contribute to the circadian transcription of genes specifying
acyl-CoA thioesterases, leading to a cyclic release of
fatty acids from thioesters. In turn, the
fatty acids act as
ligands for PPARα, and the activated PPARα receptor then stimulates the transcription of genes encoding
proteins involved in the uptake and/or metabolism of
lipids,
cholesterol, and
glucose metabolism.