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Genome wide association studies have identified Tribbles-1 (TRIB1) to be significantly associated with all major plasma lipid traits and as a risk factor for ischaemic heart disease and myocardial infarction. Studies in mice using Trib1 full body KO and liver-specific over-expression and KO models have shown that hepatic expression of TRIB1 reduces circulating lipids. Additionally, Trib1 has been implicated as a regulator of alternatively activated macrophages. However the potential interplay between hepatocytes, macrophages and Trib1 remain unexplored.This study aimed to assess whether myeloid Trib1 regulates tissue macrophage polarisation and investigate its consequences on plasma lipid homeostasis.We developed myeloid specific Trib1 conditional knockout (Trib1 fl/fl x Lyz2Cre; Trib1KO) and over-expressor mice (ROSA26Trib1.Tg x Lyz2Cre; Trib1Tg), thereby deleting or over-expressing Trib1 in myeloid cells. Plasma lipid levels were directly measured by ion mobility. Macrophage phenotype was characterised in the liver (Kupffer cells, KCs), adipose (ATMs) and BMDMs by qPCR and semi-quantitative immunofluorescence analysis. Western blotting was used to assess regulators of macrophage polarisation. Furthermore, microarray analysis of human monocyte derived macrophages (MDMs) was employed to identify potential TRIB1-regulated cytokines.Loss of myeloid Trib1 increased levels of plasma triglyceride, VLDL-C (p<0.05) and promoted pro-inflammatory polarisation in KCs (p<0.01), ATMs (p<0.01) and BMDMs (p<0.05), while Trib1Tg mice revealed opposing changes in all parameters assessed. Western blotting showed TRIB1 modulates protein levels of C/EBP-β2 and –β² (p<0.05), both key regulators of macrophage polarisation, via the control of COP1 activity and miR-155 expression. Microarray analysis of MDMs indicated TRIB1 may regulate production of a number of pro-inflammatory cytokines that are implicated in fatty liver disease and adipocyte lipolysis. Reduced expression of these was confirmed in in Trib1Tg BMDMs (p<0.05).Myeloid Trib1 is a potent regulator of lipid homeostasis, the loss of which promotes inflammation in metabolic tissues. Our observations uncover a novel mechanism of KC-hepatocyte cross talk mediated through Trib1.