Hepatic steatosis or fatty liver is considered the key metabolic precursor to non-alcoholic fatty liver disease (NAFLD), the major cause of liver-associated illness and death in the United States. Disease progression in NAFLD is currently thought to be triggered by an acute insult (the """"""""second hit"""""""") that is imposed on hepatic steatosis (the """"""""first hit""""""""). However, a precise understanding of the molecular basis by which the """"""""two hits"""""""" trigger the transition from reversible steatosis to NAFLD remains elusive. Previously, we revealed a novel liver- specific transcription factor CREBH (cyclic-AMP-response-element-binding protein H), which is activated by endoplasmic reticulum (ER) stress to mediate an acute-phase inflammatory response in the liver. Recently, we have accumulated strong preliminary evidence that CREBH plays a crucial role in regulating hepatic lipid homeostasis under metabolic stress conditions. Saturated fatty acids, inflammatory stimuli, or high-fat feeding can induce cleavage of CREBH in vitro or in vivo, leading to its activation. Deletion of CREBH in mice resulted in decreased expression of key lipogenic enzymes and reduced hepatic lipid accumulation in response to acute ER stress or atherogenic high-fat feeding. After the high-fat feeding for 6 months, CREBH null mice displayed significantly less hepatic steatosis and inflammation but greater insulin sensitivity and glucose tolerance, compared to the control mice. Furthermore, CREBH was found to activate expression of key lipogenic regulators, including CCAAT-enhancer-binding protein beta (C/EBP2) and peroxisome proliferator- activated receptor gamma (PPAR3), in liver hepatocytes under the metabolic stress. These observations lead to the central hypothesis of this proposal: metabolic stress, induced by excessive saturated fatty acids or pro- inflammatory cytokines, activates CREBH;activated CREBH then functions as a lipogenic transcriptional regulator to propagate hepatic steatosis and steatohepatitis. In this grant application, we will elucidate the pathophysiologic role and molecular mechanism of CREBH in regulating hepatic steatosis and the development of NAFLD. To achieve our research goal, we will pursue three complementary specific aims: (1) to delineate the regulatory mechanism by which metabolic factors, including saturated fatty acids and pro- inflammatory cytokines, activate CREBH;(2) to decipher the molecular basis of CREBH-mediated stress signaling in regulating hepatic lipid homeostasis;(3) to determine the role of CREBH in the transition of hepatic steatosis to steatohepatitis under the metabolic stress. This work represents a novel avenue to elucidate ER stress-associated mechanisms in hepatic steatosis and steatohepatitis that are currently poorly understood. Completion of the proposed studies will not only define the molecular basis by which a novel, stress-induced transcription factor regulates hepatic lipid metabolism, but will also be significant for designing new strategies for the prevention and treatment of human NAFLD and its associated metabolic syndromes.

Public Health Relevance

Non-alcoholic fatty liver disease (NAFLD), the major cause of liver-associated illness and deaths, frequently precedes or co-exists with obesity, type II diabetes, and cardiovascular disease. This project will identify the regulatory mechanisms by which a novel stress-inducible transcription factor CREBH promotes fatty liver and progression of NAFLD under metabolic stress. Understanding the stress-induced molecular mechanisms in hepatic lipid accumulation and its associated pathogenesis is a key prerequisite for the development of new diagnostics and therapeutics targeting NAFLD.

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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