Circadian clock orchestrates diverse physiological processes that are critical for health and disease. Cyclic AMP responsive element-binding protein, hepatocyte-specific (CREBH) is a liver-enriched, endoplasmic reticulum (ER)-tethered transcription factor known to regulate hepatic acute-phase response and energy homeostasis under stress conditions. Here, we demonstrate that CREBH is regulated by the circadian clock and functions as a circadian regulator of hepatic lipid metabolism. Proteolytic activation of CREBH in the liver exhibits typical circadian rhythmicity that is controlled by the core clock oscillator BMAL1 and AKT/GSK3β signaling pathway. GSK3β-mediated phosphorylation of CREBH modulates the association between CREBH and the Coat Protein Complex II (COPII) transport vesicle, and thus controls the ER to Golgi transport and subsequent proteolytic cleavage of CREBH in a circadian manner. Functionally, CREBH regulates circadian expression of the key genes involved in triglycerides (TG) and fatty acid (FA) metabolism, and is required to maintain circadian amplitudes of blood TG and FA in mice. During the circadian cycle, CREBH rhythmically regulates, and interacts with, the hepatic nuclear receptors PPARα and LXRα as well as the circadian oscillation activator DBP and the repressor E4BP4 to modulate CREBH transcriptional activities. In conclusion, our studies revealed that CREBH functions as a circadian-regulated liver transcriptional regulator that integrates energy metabolism with circadian rhythm.
- Received March 3, 2016.
- Accepted August 2, 2016.
- © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.