Open Access Dissertation
Date of Award
Molecular Biology and Genetics
Lipid metabolism is tightly regulated by nuclear receptors, transcription factors, and cellular enzymes in response to nutritional, hormonal, and stress signals. Hepatocyte specific, cyclic AMP responsive element-binding protein (CREBH) is a transcription factor that is preferentially expressed in the liver and localized in the endoplasmic reticulum (ER) membrane. CREBH is known to be activated by ER stress, inflammatory stimuli, and metabolic signals to regulate hepatic acute-phase response, lipid metabolism, and glucose metabolism. In my thesis research, I have characterized the roles and mechanisms of CREBH in these functions, as well as the overall phenotype of CrebH-null mice. I demonstrated that CREBH interacts with peroxisome proliferator-activated receptor alpha (PPARA) to regulate expression of the genes involved in lipolysis, FA oxidation, and ketogenesis by activating fibroblast growth factor 21 (FGF21), a hepatic hormone that regulates whole-body energy homeostasis. Gain- and loss-of-function analyses indicated that CREBH and PPARA regulate each other for their expression. Activated CREBH protein interacts with PPARA under fasting or metabolic diet, and both factors are required for induction of the FGF21 gene. CREBH and PPARA bind to integrated CREH-PPARA binding motifs in the FGF21 gene promoter across mammalian species. CREBH and PPARA function in synergy to activate the FGF21 gene promoter. Administration of recombinant human FGF21 protein can rescue hypertriglyceridemia and hypoketonemia and, partially, nonalcoholic steatohepatitis (NASH) in the CrebH-null mice developed under an atherogenic high-fat diet, corroborating the role of CREBH in regulating FGF21. In summary, my research demonstrated the transcriptional mechanism for CREBH in regulating lipid metabolism by activating FGF21. In particular, the functional interaction between CREBH and PPARA in regulating FGF21 may represent an important transcriptional coactivation mechanism in maintaining lipid homeostasis under metabolic stress.
Mendez, Roberto, "The Role Of Crebh In Hepatic Energy Regulation Under Metabolic Stress" (2015). Wayne State University Dissertations. 1154.