Toll-like Receptor (TLR) Signaling Interacts with CREBH to Modulate High-density Lipoprotein (HDL) in Response to Bacterial Endotoxin. J Biol Chem 2016 Oct 28;291(44):23149-23158
Date
10/30/2016Pubmed ID
27637329Pubmed Central ID
PMC5087733DOI
10.1074/jbc.M116.755728Scopus ID
2-s2.0-84993982959 (requires institutional sign-in at Scopus site) 16 CitationsAbstract
Bacterial endotoxin can induce inflammatory and metabolic changes in the host. In this study, we revealed a molecular mechanism by which a stress-inducible, liver-enriched transcription factor, cAMP-responsive element-binding protein hepatic-specific (CREBH), modulates lipid profiles to protect the liver from injuries upon the bacterial endotoxin lipopolysaccharide (LPS). LPS challenge can activate CREBH in mouse liver tissues in a toll-like receptor (TLR)/MyD88-dependent manner. Upon LPS challenge, CREBH interacts with TNF receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase that functions as a key mediator of TLR signaling, and this interaction relies on MyD88. Further analysis demonstrated that TRAF6 mediates K63-linked ubiquitination of CREBH to facilitate CREBH cleavage and activation. CREBH directly activates expression of the gene encoding Apolipoprotein A4 (ApoA4) under LPS challenge, leading to modulation of high-density lipoprotein (HDL) in animals. CREBH deficiency led to reduced production of circulating HDL and increased liver damage upon high-dose LPS challenge. Therefore, TLR/MyD88-dependent, TRAF6-facilitated CREBH activation represents a mammalian hepatic defense response to bacterial endotoxin by modulating HDL.
Author List
Dandekar A, Qiu Y, Kim H, Wang J, Hou X, Zhang X, Zheng Z, Mendez R, Yu FS, Kumar A, Fang D, Sun F, Zhang KAuthor
Ze Zheng PhD Assistant Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBacteria
Bacterial Infections
Contraindications
Cyclic AMP Response Element-Binding Protein
Endotoxins
Humans
Lipopolysaccharides
Lipoproteins, HDL
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Differentiation Factor 88
Protein Binding
Signal Transduction
TNF Receptor-Associated Factor 6
Toll-Like Receptor 4