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Diabetes. 2016 Nov;65(11):3369-3383. Epub 2016 Aug 9.

CREBH Couples Circadian Clock With Hepatic Lipid Metabolism.

Author information

1
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI.
2
Department of Physiology, Wayne State University School of Medicine, Detroit, MI.
3
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI.
4
Department of Biological Sciences, University of Memphis, Memphis, TN.
5
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI.
6
Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI.
7
Department of Anatomy & Cell Biology, Wayne State University School of Medicine, Detroit, MI.
8
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI.
9
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI kzhang@med.wayne.edu.

Abstract

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.

PMID:
27507854
PMCID:
PMC5079639
DOI:
10.2337/db16-0298
[Indexed for MEDLINE]
Free PMC Article

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