Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.770242
Title: The impact and regulatory function of Tribbles on metabolic homeostasis
Author: Ilyas, Zabran
ISNI:       0000 0004 7651 7946
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2019
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Abstract:
Metabolic syndrome significantly increases the risk of developing chronic inflammatory diseases including coronary artery disease, stroke and type 2 diabetes. Obesity is a major risk factor for many facets of metabolic diseases which lead to significant morbidity and mortality worldwide. The family of Tribbles pseudokinases, including Trib3 have been implicated in the development of many chronic inflammatory diseases. Previous human genetic studies have shown a Q84R polymorphism of TRIB3 to be associated with insulin resistance, dyslipidaemia and increased risk of developing diabetes. Furthermore, patients with type 2 diabetes (T2DM) were shown to have elevated levels of TRIB3 in the pancreas compared with healthy patients. TRIB3 was also implicated in the diabetic atherosclerosis process. Silencing Trib3 in apolipoprotein E (apoE)/LDR receptor (LDLR) double-knockout (ApoE–/– /LDLR–/– ) mice with diabetes reduced atherosclerotic burden and stabilised the plaque in mice. All the evidence above indicates that Trib3 is an important regulator of insulin resistance and cardiovascular disease. However, the mechanisms of how Trib3 plays a part in chronic inflammatory diseases are unexplored. Development of metabolic syndrome is driven by a combination of different metabolic tissues becoming dysfunctional. While it is clear that the various organs may be affected differently, our insights into the role of Trib3 in various organs remains limited. This study is aimed to use a systemic approach, for the first time on a whole body Trib3ko mice to decipher a role for Trib3 in metabolic dysfunction. Full body Trib3ko mice were created using the gene-trap system. Male Trib3ko mice were obese with elevated plasma levels of HDL and total cholesterol. These knockout mice also displayed a fatty liver phenotype, an increased macrophage influx in the liver and dysregulated proliferation in the adipose tissue. Comparative gene expression microarray analysis was performed on the liver, adipose and muscle tissues from Trib3 ko and WT littermates. Gene Ontology and Pathway Analysis were performed using Ingenuity Pathway Analysis software. This analysis revealed multiple metabolic pathways in the liver, adipose and muscle tissues were altered, suggesting a dysregulated inter organ communication underpinning obesity. Key signalling regulators, such as PPARa, CEBPa and Akt were altered in the liver of Trib3ko compared with WT mice as evidenced by qPCR and western blots. Interestingly, a concurrent increase in GLUT2 levels were detected in Trib3ko liver, pointing to a possible crossregulation between liver lipid and glucose metabolisms via Trib3. Although Trib3 is implicated in lipid metabolism and insulin resistance, the isoform Trib1 has also been described as a regulator of inflammatory signalling and lipid metabolism. A genome-wide association study (GWAS) in a human patient had shown Trib1 to be associated with hyperlipidaemia and increase the risk of developing coronary artery disease (CAD) Trib1 has also shown to be an important negative regulator of inflammation and acts to lower plasma lipid levels. The half-life of Trib1 mRNA is < 1 h, so the aim of the second part of the project was to find ways to stabilise Trib1 mRNA levels which would, therefore, have beneficial effects on lipogenesis. The liver is the primary organ to modulate systemic cholesterol levels, so the aim was to stabilise TRIB1 levels in the liver. miRNA202 was shown to be a novel small non-coding RNA which can modulate TRIB1 protein levels, therefore representing a target by which TRIB1 levels could be raised in vivo, providing a mechanism to augment lipid levels and therefore the antiatherosclerotic effects of this protein.
Supervisor: Kiss-Toth, Endre ; Tan Nguan Soon, Andrew Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.770242  DOI: Not available
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