| Summary: | 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.
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