Bone marrow deficiency of mRNA decaying protein Tristetraprolin increases inflammation and mitochondrial ROS but reduces hepatic lipoprotein production in LDLR knockout mice

Redox Biology

Junfeng Wang¹  Stephen Iwanowycz²  Susan M. Lessner²  Perry J. Blackshear³  Yuzhen Wang⁴  Diego Altomare⁴  Xiaofeng Yang⁴  Fatma Saaoud⁴  Ying Shao⁴  Jianguo Liu⁵  Daping Fan⁶  E. Angela Murphy⁷  Hong Wang⁸ 

[1] Centers for Inflammation, Translational &Clinical Lung Research, Departments of Microbiology and Immunology and Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 14190, USA;;Centers for Inflammation, Translational &Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, 29209, USA;Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA;Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29209, USA;Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA;Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA;

关键词: Tristetraprolin;    Lipid metabolism;    Lipoprotein;    Inflammation;    Atherosclerosis;    Hepatic steatosis;   

DOI  :  

来源: DOAJ

【 摘 要 】

Tristetraprolin (TTP), an mRNA binding and decaying protein, plays a significant role in controlling inflammation by decaying mRNAs encoding inflammatory cytokines such as TNFalpha. We aimed to test a hypothesis that TTP in bone marrow (BM) cells regulates atherogenesis by modulating inflammation and lipid metabolism through the modulation of oxidative stress pathways by TTP target genes. In a BM transplantation study, lethally irradiated atherogenic LDLR−/− mice were reconstituted with BM cells from either wild type (TTP+/+) or TTP knockout (TTP−/−) mice, and fed a Western diet for 12 weeks. We made the following observations: (1) TTP−/− BM recipients display a significantly higher systemic and multi-organ inflammation than TTP+/+ BM recipients; (2) BM TTP deficiency modulates hepatic expression of genes, detected by microarray, involved in lipid metabolism, inflammatory responses, and oxidative stress; (3) TTP−/− BM derived macrophages increase production of mitochondrial reactive oxygen species (mtROS); (4) BM-TTP−/− mice display a significant reduction in serum VLDL/LDL levels, and attenuated hepatic steatosis compared to controls; and (5) Reduction of serum VLDL/LDL levels offsets the increased inflammation, resulting in no changes in atherosclerosis. These findings provide a novel mechanistic insight into the roles of TTP-mediated mRNA decay in bone marrow-derived cells in regulating systemic inflammation, oxidative stress, and liver VLDL/LDL biogenesis.

【 授权许可】

Unknown