8q24.13

C8FW,GIG-2,GIG2,SKIP1,TRB-1,TRB1

Smooth muscle cells

TRIB1 is selectively over-expressed in chronically inflamed human atherosclerotic arteries and regulates vascular smooth muscle cell (VSMC) chemotaxis and proliferation, a characteristic feature of atherosclerosis via the JNK pathway (Sung, et al 2007).

Macrophages

Trib1 is expressed in plaque resident macrophages in murine experimental atherosclerosis. The expression of Trib1 could be upregulated by IL-1, a major contributor to plaque development as the percentage of Trib1 expressing macrophages significantly decreases in ApoE -/- IL1R-/- double knockout mice compared to ApoE-/- controls. Overexpression of Trib1 in macrophages in vitro also leads to a significant attenuation (~70%) of IL-6 production and suppressed IL-12 expression induced with a pro-inflammatory stimulus (Sung, et al 2012).
It has also been shown that TRIB1 is involved in macrophage migration through interactions with C/EBP β and TNF- α. Knockdown of TRIB1 in RAW246.7 cells resulted in an increase in TNF- α production and C/EBPβ expression suggesting TRIB1 may modulate TNF- α through C/EBP β (Liu, et al 2013).
Trib1 has been shown to also be involved with adipose tissue maintenance and suppression of metabolic disorders by controlling the differentiation of tissue M2-like macrophages. Trib1 deficiency results in a significant reduction of M2-like macrophages. Mice lacking Trib1 in haematopoietic cells show a reduced adipocyte tissue mass and have evidence of increased lipolysis even on a normal diet. Supplementation of M2-like macrophages causes rescue suggesting the lack of these M2-like macrophages are responsible for lipolysis. When mice are fed a high fat diet, mice lacking Trib1 in haematopoietic cells develop hypertriglyceridaemia and insulin resistance and a pro-inflammatory cytokine induction (Satoh, et al 2013).

Cancer

TRIB1 has been associated with the development of cancer and is considered as a leukaemia disease gene. It was identified as a collaborator of Hoxa9 and Meis1 in myeloid leukaemogenesis (Jin, et al 2007). Cooperative genes for Hoxa9/Meis1 were identified as common targets for retroviral integration, where TRIB1 was identified as the most frequent common site for integration in AML (Nakamura 2005). Table 5 shows the common integration sites and candidate cooperative genes in TRIB1-induced AML (Yokoyama and Nakamura 2011). TRIB1 alone is a transforming gene for myeloid cells and also significantly accelerates the development of Hoxa9/Meis1 AML.

Phosphorylation of ERK is enhanced in TRIB1 transfected HeLa and Baf3 cells and leukaemia cells derived from TRIB1-induced AML upon cytokine stimulation (Jin, et al 2007).
MEK1 and enhancement of MEK/ERK phosporylation is required for reactivity. Mutant lacking MEK1 binding site is unable to enhance phosphorylation of ERK or extend self renewal in bone marrow cells or induce AML/accelerate Hoxa9/Meis1 induced AML (Yokoyama, et al 2010).
TRB1 has been implicated in human AML. TRIB1 is found on chromosome 8q24, 1.5Mb away from c-MYC, the target of AML amplification. TRIB1 is over-expressed even in some cases of AML when c-MYC amplification is not detected (Roethlisberger, et al 2007, Storlazzi, et al 2006)

Cardiovascular Disease and Atherosclerosis

Emerging evidence from several genome-wide association studies (GWAS) has implicated TRIB1 in the risk of cardiovascular disease and events specifically due to the levels of circulating lipids (Kathiresan, et al 2008, Willer, et al 2008).
Two SNPs (rs2954029 and rs17321515) near the TRIB1 gene have been implicated with triglyceride, LDL and HDL levels. A minor G allele at rs17321515 was associated with lower triglyceride and LDL cholesterol and higher HDL cholesterol levels. A TT -> TA -> AA genotypes at rs2954029 were associated with step wise increases in the levels of triglyceride, remnant cholesterol and apo-lipoprotein B, the primary apolipoproteins present on LDLs. Likewise HDL cholesterol levels decreased step-wise through the genotypes. Additionally the genotypes were found to be significantly associated with increased risk of ischemic heart disease (IHD) and increased risk of MI
Further bivariate analysis showed TRIB1 expression to be significantly associated with triglyceride/ elevated blood pressure and triglyceride/HDL-cholesterol suggesting TRIB1 may be involved in a specific feature of lipid homeostasis (Kraja, et al 2011).
These genetic studies were further validated in in vivo models. Specific hepatic over-expression of Trib1 using an adenovirus vector reduced lipid plasma levels in a dose-dependent manner due to reduced VLDL production. Equally the opposite was seen in Trib1- knockout mice due to increased VLDL production. Interestingly when hepatic expression was reconstituted in knockout mice, VLDL-triglyceride production decreased to levels found in control mice (Burkhardt, et al 2010). The precise mechanisms of Trib1 involvement in lipid metabolism however are unknown.
Burkhardt, et al (2010) further investigated by examining the mRNA levels of genes associated with lipid metabolism in the livers of Trib1 over-expressing and Trib1- deficient mice. A significant decrease was found for genes involved in fatty acid oxidation such as Cpt1a (carnitine palmitoyltransferase 1A), Cpt2, and Acox1 (acyl-Coenzyme A oxidase 1) in Trib1 -/- mice. A significant up-regulation of key lipogeneic genes was also found such as Acc1 (acetyl-Coenzyme A carboxylase), fatty acid synthesis (Fasn) and stearoyl-Coenzyme A desaturase 1(Scd1). Significant downregulation of these genes were found in Trib1-over expressing mice. These genes have been noted to have effects on VLDL secretion and plasma triglyceride and cholesterol levels.
TRIB1 may also have a further role in lipogenesis. TRIB1 over-expression resulted in a significant decrease in 35S-methionine labelled apoB secretion in HepG2 cells (human liver carcinoma cell line). The authors speculate that TRIB1-mediated regulation of hepatic lipid availability might alter the secretion of apoB particles via a mechanism involving ER-associated degradation (ERAD) as previous data has shown a reduced availability or synthesis of lipid for apoB lipidation leads to co-translational targeting of apoB for ERAD (Ginsberg, et al 2009).

Type 2 Diabetes

Trib1 has been hypothesised to have a regulatory role in inflammation in adipoctyes that may contribute towards obesity related type 2 diabetes. Trib1 is specifically up-regulated during acute and chronic inflammation in white adipose tissue in mice. Trib1 knockout mice show it to be a key regulator of inflammatory cytokines such as TNF-a and are protected from high fat diet induced obesity (Ostertag, et al 2010). It is proposed that Trib1 is pro-inflammatory in the adipose by acting as a co-activator for NF-kB inducing the expression of proinflammatory cytokines.