Access Type

Open Access Dissertation

Date of Award

January 2015

Degree Type


Degree Name



Molecular Biology and Genetics

First Advisor

Kezhong Zhang


Circadian rhythms play crucial roles in orchestrating diverse physiological processes that are critical for health and disease. Cyclic AMP responsive element binding protein 3-like 3 (CREB3L3, also known as 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 diurnal regulator of hepatic lipid and glucose metabolism. CREBH is required to maintain circadian profiles of blood triglycerides, fatty acids, and glucose as well as hepatic glycogen storage. CREBH rhythmically regulates expression levels and amplitudes of the key genes involved in bi-directional metabolic pathways of both energy utilization and storage. CREBH regulates, and interacts with, the circadian transcriptional activators PPARα and C/EBPβ or the repressor E4BP4 to modulate CREBH transcriptional activities. CREBH deficiency leads to hyper-locomotion, increased metabolic rates, and phase-shifted feeding behavior in mice. In summary, our studies reveal that CREBH functions as a liver metabolic regulator that integrates energy metabolism with circadian rhythm.