CREBH Maintains Circadian Glucose Homeostasis by Regulating Hepatic Glycogenolysis and Gluconeogenesis

May 3, 2017Molecular and cellular biology

CREBH helps keep daily blood sugar balance by controlling liver sugar breakdown and production

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Abstract

CREBH is identified as a key metabolic regulator that controls glucose homeostasis across the circadian cycle.

CREBH is a liver-specific transcription factor that regulates the body's response to stress and lipid levels.
Its activity is influenced by the circadian clock, affecting processes related to glucose storage and release.
The rhythmic expression of key enzymes involved in glucose production and storage is controlled by CREBH.
CREBH interacts with another protein, PPARα, enhancing its ability to regulate glucose metabolism.
Deficiency in CREBH results in lower blood glucose levels and higher glycogen levels in the liver, particularly during the day or fasting.

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Cyclic AMP-responsive element binding protein, hepatocyte specific (CREBH), is a liver-enriched, endoplasmic reticulum-tethered transcription factor known to regulate the hepatic acute-phase response and lipid homeostasis. In this study, we demonstrate that CREBH functions as a circadian transcriptional regulator that plays major roles in maintaining glucose homeostasis. The proteolytic cleavage and posttranslational acetylation modification of CREBH are regulated by the circadian clock. Functionally, CREBH is required in order to maintain circadian homeostasis of hepatic glycogen storage and blood glucose levels. CREBH regulates the rhythmic expression of the genes encoding the rate-limiting enzymes for glycogenolysis and gluconeogenesis, including liver glycogen phosphorylase (PYGL), phosphoenolpyruvate carboxykinase 1 (PCK1), and the glucose-6-phosphatase catalytic subunit (G6PC). CREBH interacts with peroxisome proliferator-activated receptor α (PPARα) to synergize its transcriptional activities in hepatic gluconeogenesis. The acetylation of CREBH at lysine residue 294 controls CREBH-PPARα interaction and synergy in regulating hepatic glucose metabolism in mice. CREBH deficiency leads to reduced blood glucose levels but increases hepatic glycogen levels during the daytime or upon fasting. In summary, our studies revealed that CREBH functions as a key metabolic regulator that controls glucose homeostasis across the circadian cycle or under metabolic stress.

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CREBH Maintains Circadian Glucose Homeostasis by Regulating Hepatic Glycogenolysis and Gluconeogenesis

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