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Saaoud F , Wang J , Iwanowycz S , Wang Y , Altomare D , Shao Y , Liu J , Blackshear PJ , Lessner SM , Murphy EA , Wang H , Yang X , Fan D
Bone marrow deficiency of mRNA decaying protein Tristetraprolin increases inflammation and mitochondrial ROS but reduces hepatic lipoprotein production in LDLR knockout mice
Redox Biol. 2020 Jun 17 :101609
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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.
2213-2317 Saaoud, Fatma Wang, Junfeng Iwanowycz, Stephen Wang, Yuzhen Altomare, Diego Shao, Ying Liu, Jianguo Blackshear, Perry J Lessner, Susan M Murphy, E Angela Wang, Hong Yang, Xiaofeng Fan, Daping Journal Article Netherlands Redox Biol. 2020 Jun 17:101609. doi: 10.1016/j.redox.2020.101609.