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 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.