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 interaction and synergism in regulating circadian metabolism. The findings from our proposed research will have important implications in the prevention and treatment of metabolic disease.

Public Health Relevance

Non-alcoholic fatty liver disease (NAFLD) and hyperlipidemia are major metabolic disorders that frequently precede or co-exist with type-2 diabetes and cardiovascular disease. Irregular circadian rhythm due to the modern life style is closely associated with human NAFLD and hyperlipidemia. This project will identify a major molecular link mediated through the hepatic transcription factor CREBH that integrates circadian regulation to liver energy metabolism and elucidate the pathophysiological impact of this link in the development of NAFLD and hyperlipidemia. Delineating the molecular basis and physiological significance of liver circadian metabolism will have a major impact in the prevention and treatment of human metabolic disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Doo, Edward
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Wayne State University
Schools of Medicine
United States
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Zhang, Kezhong; Kim, Hyunbae; Fu, Zhiyao et al. (2018) Deficiency of the Mitochondrial NAD Kinase Causes Stress-Induced Hepatic Steatosis in Mice. Gastroenterology 154:224-237
Wei, Juncheng; Chen, Lu; Li, Fei et al. (2018) HRD1-ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination. EMBO J 37:
Bhattacharya, Asmita; Sun, Shengyi; Wang, Heting et al. (2018) Hepatic Sel1L-Hrd1 ER-associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH. EMBO J 37:
Zhang, Kezhong (2018) ""NO"" to Autophagy: Fat Does the Trick for Diabetes. Diabetes 67:180-181
Wang, Jie-Mei; Qiu, Yining; Yang, Zhao et al. (2018) IRE1? prevents hepatic steatosis by processing and promoting the degradation of select microRNAs. Sci Signal 11:
Wang, Jie-Mei; Qiu, Yining; Yang, Zeng-Quan et al. (2017) Inositol-Requiring Enzyme 1 Facilitates Diabetic Wound Healing Through Modulating MicroRNAs. Diabetes 66:177-192
Hou, Xia; Yang, Zhao; Zhang, Kezhong et al. (2017) SUMOylation represses the transcriptional activity of the Unfolded Protein Response transducer ATF6. Biochem Biophys Res Commun 494:446-451
Yang, Zhao; Kim, Hyunbae; Ali, Arushana et al. (2017) Interaction between stress responses and circadian metabolism in metabolic disease. Liver Res 1:156-162
Kim, Hyunbae; Zheng, Ze; Walker, Paul D et al. (2017) CREBH Maintains Circadian Glucose Homeostasis by Regulating Hepatic Glycogenolysis and Gluconeogenesis. Mol Cell Biol 37:
Qiu, Yining; Zheng, Ze; Kim, Hyunbae et al. (2017) Inhalation Exposure to PM2.5 Counteracts Hepatic Steatosis in Mice Fed High-fat Diet by Stimulating Hepatic Autophagy. Sci Rep 7:16286

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