# Regulation of Circadian Metabolism by the Hepatic Transcription Factor CREBH

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2020 · $302,490

## Abstract

PROJECT SUMMARY
 Dysregulated circadian rhythm is closely associated with human metabolic disease, such as type-2 diabetes,
cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Due to the modern life style, the problem
of irregular circadian rhythm has enormous impact in public health. Although considerable progress has been
made in understanding the connection between circadian rhythm and metabolism, the mechanisms by which
circadian regulators modulate metabolic rhythmicity and its impact in the progression of metabolic disorders
remain to be further elucidated. During the last funding cycle, we defined an endoplasmic reticulum (ER)-resident,
liver-specific transcription factor named CREBH (cyclic-AMP-response element-binding protein H) that can be
activated by a variety of inflammatory and metabolic signals to function as a key regulator of hepatic energy
metabolism. Recently, we have accumulated strong preliminary evidence that CREBH functions as an organ-
specific, diurnal regulator that is critical for preserving the rhythmicity of energy homeostasis. During the circadian
cycle, CREBH activation in the liver is regulated by the core clock oscillator BMAL1, and activated CREBH
interacts with the key circadian metabolic regulators to regulate diurnal rhythm of lipid and glucose homeostasis.
CREBH-deficient mice display impaired rhythmic profiles of lipids and glucose and altered metabolic responses,
and are susceptible to the development of hepatic steatosis and hyperlipidemia. These observations led to our
central hypothesis that CREBH functions as a key transcriptional regulator in the liver that integrates circadian
regulation to hepatic energy homeostasis. Disruption of CREBH-regulated hepatic energy rhythmicity contributes
to or amplifies NAFLD and hyperlipidemia under the metabolic diet or shift working/feeding conditions. To test
this hypothesis, we will utilize molecular and cellular approaches, animal genetics, and circadian metabolic
studies to address the molecular mechanism and pathophysiological significance for CREBH-regulated
metabolic rhythmicity in the progression of NAFLD and hyperlipidemia. We will pursue two complementary
specific aims: Aim 1, to determine the circadian regulation of CREBH and its role in preserving circadian
rhythmicity of energy homeostasis in both physiological and pathological settings; Aim 2, to decipher the
molecular mechanisms by which CREBH integrates circadian regulation to hepatic energy metabolism. Within
the funding period, we anticipate providing significant insights into the molecular mechanism underlying the
integration of circadian regulation to energy metabolism, in which CREBH plays a key role, and determining the
pathophysiological impact of the defined molecular network in metabolic syndrome. Our proposed research will
significantly extend our understanding of the functional relationship between stress-inducible trans-activators
and nuclear receptors and their interact...

## Key facts

- **NIH application ID:** 9913501
- **Project number:** 5R01DK090313-10
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Kezhong Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $302,490
- **Award type:** 5
- **Project period:** 2011-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913501

## Citation

> US National Institutes of Health, RePORTER application 9913501, Regulation of Circadian Metabolism by the Hepatic Transcription Factor CREBH (5R01DK090313-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9913501. Licensed CC0.

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