CREBH Couples Circadian Clock With Hepatic Lipid Metabolism

Aug 11, 2016Diabetes

CREBH Links the Body's Daily Clock to Liver Fat Processing

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

CREBH regulates hepatic lipid metabolism in a circadian manner.

CREBH's activation in the liver follows a daily rhythm influenced by the core clock component BMAL1 and specific signaling pathways.
Phosphorylation of CREBH by GSK3β impacts its transport and activation related to lipid metabolism.
CREBH influences the expression of genes involved in triglyceride and fatty acid metabolism in a circadian rhythm.
The protein interacts with nuclear receptors and oscillation regulators to modulate its transcriptional activities throughout the day.
Maintaining rhythmic activity of CREBH is important for regulating blood triglyceride and fatty acid levels in mice.

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The circadian clock orchestrates diverse physiological processes critical for health and disease. CREB, hepatocyte specific (CREBH) is a liver-enriched, endoplasmic reticulum (ER)-tethered transcription factor known to regulate the hepatic acute phase response and energy homeostasis under stress conditions. 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 controlled by the core clock oscillator BMAL1 and AKT/glycogen synthase kinase 3β (GSK3β) signaling pathway. GSK3β-mediated phosphorylation of CREBH modulates the association between CREBH and the coat protein complex II 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 triglyceride (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 peroxisome proliferator-activated receptor α and liver X receptor α as well as with the circadian oscillation activator DBP and the repressor E4BP4 to modulate CREBH transcriptional activities. In conclusion, these studies reveal that CREBH functions as a circadian-regulated liver transcriptional regulator that integrates energy metabolism with circadian rhythm.

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CREBH Couples Circadian Clock With Hepatic Lipid Metabolism

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