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.

Keywords: Atherosclerosis; Bone marrow transplantation (BMT); Hepatic steatosis; Inflammation; Lipid metabolism; Lipoprotein; Mitochondrial oxidative stress; Tristetraprolin.