Open Access Dissertation
Date of Award
Immunology and Microbiology
Bacterial endotoxins can induce a variety of physiological changes in the host. This effect is not only restricted to inflammatory changes but also comprises metabolic changes in the host body. Lipopolysaccharide (LPS), one of the key components of the bacterial cell walls, is capable of triggering host metabolic changes. Hyperlipidemia usually accompanies with high endotoxin levels as well as inflammation. Lipid metabolism disorders are one of the common hallmarks of a patient with sepsis or high levels of endotoxin through diet. Previously, we have identified an endoplasmic reticulum (ER) anchored liver-specific transcription factor CREBH (cAMP-responsive element-binding protein, hepatocyte-specific), which is activated by ER stress, inflammatory stimuli, and metabolic signals. Proinflammatory cytokines TNFα, IL6, and IL1β, bacterial endotoxin lipopolysaccharide, insulin signal, saturated fatty acids, nutrient starvation, or atherogenic high-fat (AHF) feeding, can all induce expression and/or activation of CREBH in the liver. In this study, we demonstrate that CREBH acts a key player in mounting an acute phase response against endotoxemia by modulating apolipoproteins. Endotoxin LPS shock in the body induces activation of the TLR4 signaling pathway in mouse liver. Upon triggering TLR4 signaling pathway, LPS stimulates cleavage and activation of CREBH transcription factor LPS induces the interaction between CREBH and TNF receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase that plays a key role in mediating TLR signaling. While LPS-induced TRAF6-CREBH interaction relies on MyD88, TRAF6 mediates the ubiquitination of CREBH to facilitate CREBH activation upon LPS challenge. Functionally, CREBH directly activates expression of the gene encoding Apolipoprotein (Apo) A IV and IL6 under LPS challenge, leading to modulation of high-density lipoprotein (HDL) in animal models. In summary, my study suggested that TLR-dependent, LPS-induced CREBH activation may represent a host defense response to bacterial endotoxin by modulating apolipoproteins. Targeting the expression of CREBH under disease condition may represent a novel approach towards alleviating the sepsis-related complications.
Dandekar, Aditya Prakash, "Role Of Crebh In Endotoxin Mediated Modulation Of Hepatic Metabolism" (2015). Wayne State University Dissertations. 1308.