title: Toll-like Receptor (TLR) Signaling Interacts with CREBH to Modulate High-density Lipoprotein (HDL) in Response to Bacterial Endotoxin.
abstract: 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.
authors.affiliation: Department of Immunology and Microbiology.
authors.forename: Aditya
authors.initials: A
authors.lastname: Dandekar
authors.affiliation: From the Center for Molecular Medicine and Genetics.
authors.forename: Yining
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: From the Center for Molecular Medicine and Genetics.
authors.forename: Hyunbae
authors.initials: H
authors.lastname: Kim
authors.affiliation: From the Center for Molecular Medicine and Genetics.
authors.forename: Jiemei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Physiology, and.
authors.forename: Xia
authors.initials: X
authors.lastname: Hou
authors.affiliation: From the Center for Molecular Medicine and Genetics.
authors.forename: Xuebao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Center for Molecular Medicine and Genetics.
authors.forename: Ze
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: From the Center for Molecular Medicine and Genetics.
authors.forename: Roberto
authors.initials: R
authors.lastname: Mendez
authors.affiliation: Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan 48201 and.
authors.forename: Fu-Shin
authors.initials: FS
authors.lastname: Yu
authors.affiliation: Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan 48201 and.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
authors.affiliation: Department of Physiology, and.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Immunology and Microbiology, kzhang@med.wayne.edu.|From the Center for Molecular Medicine and Genetics.
authors.forename: Kezhong
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001419:Bacteria / Q000378:metabolism; D001424:Bacterial Infections / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D000075202:Contraindications; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004731:Endotoxins / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism / Q000633:toxicity; D008075:Lipoproteins, HDL / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004731:Endotoxins; D008070:Lipopolysaccharides; D008075:Lipoproteins, HDL; D053594:Myeloid Differentiation Factor 88; D048029:TNF Receptor-Associated Factor 6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: cAMP response element-binding protein (CREB); endotoxin; gene transcription; high-density lipoprotein (HDL); toll-like receptor (TLR); ubiquitylation (ubiquitination)