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

ABSTRACT: 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.

SUBMITTER: Saaoud F

PROVIDER: S-EPMC7767740 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Saaoud Fatma F Wang Junfeng J Iwanowycz Stephen S Wang Yuzhen Y Altomare Diego D Shao Ying Y Liu Jianguo J Blackshear Perry J PJ Lessner Susan M SM Murphy E Angela EA Wang Hong H Yang Xiaofeng X Fan Daping D

Redox biology 20200617

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<sup>-/-</sup> mice were reconstituted wi ...[more]

PMID: 32591281

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

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

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