
-   In mice with global or hepatocyte-specific depletion of KLF6, there was a decrease in body fat content, improved glucose and insulin tolerance, and protection from high-fat diet (HFD)-induced steatosis. TRB3 mRNA expression is correlated with KLF6, as depletion of KLF6 in hepatocytes reduced TRB3 and PEPCK (PPARalpha-regulated genes), with decreased PPARalpha protein levels. This reduction is attributed to KLF6's suppression of miRNA 10b, preventing PPARalpha induction. In humans, advanced NAFLD patients show increased PEPCK mRNA and correlated TRB3 and KLF6 mRNA expression, alongside significantly downregulated miRNA 10b expression [PMID: 23353867].
-   *TRIB3* was significantly overexpressed in advanced grade hepatocellular carcinoma (HCC) tissues and was closely correlated with poor prognosis. TRIB3 contributes to the progression of HCC by activating the mitogen-activated protein kinase (MAPK) pathway [PMID: 34532390].
-   High VSX1 expression usually indicated that overall and disease-free survival were unfavorable for patients with clear cell renal cell carcinoma (ccRCC). VSX1 overexpression significantly increased the expression of TRIB3, which indicated that VSX1 promoted ccRCC invasiveness via transcriptional regulation of this gene [PMID: 36463181].
-   Lipotoxicity led to up-regulation of TRB3 gene expression in a mice model of lipid metabolism disorder (mice fed with high fat diet). The TRB3-COP1-SIRT1 pathway is implicated in insulin resistance in hepatocytes, with TRB3 promoting the ubiquitination of SIRT1 by recruiting COP1, leading to SIRT1 protein degradation [PMID: 31125554].
-   TRIB3 suppresses tumorigenesis by controlling mTORC2/AKT/FOXO signaling [PMID: 27308456].
-   TRIB3 increases cell resistance to arsenite toxicity by limiting the expression of the glutathione-degrading enzyme CHAC1 [PMID: 27526673].
-   The mRNA expression level of TRIB3 was significantly and positively correlated with shorter overall survival of endometrial cancer (EC) patients in TCGA database. TRIB3 may regulate CTNNB1 transcription by enhancing the recruitment of ELF4 to the CTNNB1 promoter. TRIB3 plays an oncogenic role in EC and positively regulates the self-renewal and tumorigenicity of EC cancer stem cells (CSCs) [PMID: 33334065].
-   TRB3 was highly expressed in lung adenocarcinoma tissues. TRB3 has a potentially carcinogenic role in lung adenocarcinoma by binding to ERK and JNK and promoting the phosphorylation of ERK and JNK. TRB3 interacts with ERK and JNK and contributes to the proliferation, apoptosis, and migration of lung adenocarcinoma cells [PMID: 31256425].
-   TRIB3 were overexpressed in human oral squamous cell carcinoma (OSCC) tissues. TRIB3 overexpression increased the phosphorylation of protein kinase B (AKT) and mammalian target of rapamycin (mTOR). TRIB3 promotes OSCC cell proliferation by activating the AKT signaling pathway [PMID: 33717256].
-   TRIB3 was upregulated in human RB tissues compared to adjacent normal tissues both at the mRNA and protein levels. TRIB3 promotes proliferation, migration, and invasion of retinoblastoma cells by activating the AKT/mTOR signaling pathway [PMID: 33896816].
-   TRIB3 interacts with beta-catenin and TCF4 to increase stem cell features of colorectal cancer stem cells and tumorigenesis [PMID: 30365932].

## Summary

TRIB3 protein, encoded by TRIB3 gene, modulates insulin signaling by directly binding to the kinase Akt, especially to its Thr-308 phosphorylation site, inhibiting its phosphorylation and subsequent activation. This interaction is key during fasting, as the resultant decrease in Akt activity leads to the upregulation of gluconeogenesis, a necessity for maintaining blood glucose levels in the absence of dietary intake. Additionally, TRIB3 can protect cells against oxidative stress, as it limits CHAC1 expression through modulation of the integrated stress response - CHAC1 is an enzyme that degrades the antioxidant glutathione, and heightened TRIB3 expression under conditions such as arsenite toxicity can prevent oxidative cell damage.

In hepatocellular carcinoma (HCC), TRIB3 overexpression is linked to disease aggravation through its role in activating the mitogen-activated protein kinase (MAPK) pathway, which is known to support cellular proliferation and survival, thus facilitating tumorigenesis. Regarding hepatic response to toxins like CCl4, TRIB3 induction is part of the hepatocyte stress response, which aims to stabilize cellular homeostasis by activating ISR pathways during acute intoxication. With metabolic syndrome and NAFLD, the upregulation of TRIB3 acts as a coping mechanism initially, intending to mitigate cell damage from lipotoxicity through its modulation of insulin signaling pathways.
