Quality tendering and contracting service design

Institute of Transport and Logistics Studies. Faculty of Economics and Business. The University of Sydne

Quality tendering and contracting service design

Institute of Transport and Logistics Studies. Faculty of Economics and Business. The University of Sydne

Organic cation transporter 1 (OCT1) modulates multiple cardiometabolic traits through effects on hepatic thiamine content.

A constellation of metabolic disorders, including obesity, dysregulated lipids, and elevations in blood glucose levels, has been associated with cardiovascular disease and diabetes. Analysis of data from recently published genome-wide association studies (GWAS) demonstrated that reduced-function polymorphisms in the organic cation transporter, OCT1 (SLC22A1), are significantly associated with higher total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels and an increased risk for type 2 diabetes mellitus, yet the mechanism linking OCT1 to these metabolic traits remains puzzling. Here, we show that OCT1, widely characterized as a drug transporter, plays a key role in modulating hepatic glucose and lipid metabolism, potentially by mediating thiamine (vitamin B1) uptake and hence its levels in the liver. Deletion of Oct1 in mice resulted in reduced activity of thiamine-dependent enzymes, including pyruvate dehydrogenase (PDH), which disrupted the hepatic glucose-fatty acid cycle and shifted the source of energy production from glucose to fatty acids, leading to a reduction in glucose utilization, increased gluconeogenesis, and altered lipid metabolism. In turn, these effects resulted in increased total body adiposity and systemic levels of glucose and lipids. Importantly, wild-type mice on thiamine deficient diets (TDs) exhibited impaired glucose metabolism that phenocopied Oct1 deficient mice. Collectively, our study reveals a critical role of hepatic thiamine deficiency through OCT1 deficiency in promoting the metabolic inflexibility that leads to the pathogenesis of cardiometabolic disease

The Hybrid Mouse Diversity Panel: a resource for systems genetics analyses of metabolic and cardiovascular traits

The Hybrid Mouse Diversity Panel (HMDP) is a collection of approximately 100 well-characterized inbred strains of mice that can be used to analyze the genetic and environmental factors underlying complex traits. While not nearly as powerful for mapping genetic loci contributing to the traits as human genome-wide association studies, it has some important advantages. First, environmental factors can be controlled. Second, relevant tissues are accessible for global molecular phenotyping. Finally, because inbred strains are renewable, results from separate studies can be integrated. Thus far, the HMDP has been studied for traits relevant to obesity, diabetes, atherosclerosis, osteoporosis, heart failure, immune regulation, fatty liver disease, and host-gut microbiota interactions. High-throughput technologies have been used to examine the genomes, epigenomes, transcriptomes, proteomes, metabolomes, and microbiomes of the mice under various environmental conditions. All of the published data are available and can be readily used to formulate hypotheses about genes, pathways and interactions

Genetic Control of Obesity and Gut Microbiota Composition in Response to High-Fat, High-Sucrose Diet in Mice

Obesity is a highly heritable disease driven by complex interactions between genetic and environmental factors. Human genome-wide association studies (GWAS) have identified a number of loci contributing to obesity; however, a major limitation of these studies is the inability to assess environmental interactions common to obesity. Using a systems genetics approach, we measured obesity traits, global gene expression, and gut microbiota composition in response to a high-fat/high-sucrose (HF/HS) diet of more than 100 inbred strains of mice. Here we show that HF/HS feeding promotes robust, strain-specific changes in obesity that is not accounted for by food intake and provide evidence for a genetically determined set-point for obesity. GWAS analysis identified 11 genome-wide significant loci associated with obesity traits, several of which overlap with loci identified in human studies. We also show strong relationships between genotype and gut microbiota plasticity during HF/HS feeding and identify gut microbial phylotypes associated with obesity

Systems genetic approach to diet-induced non-alcoholic fatty liver disease (NAFLD), 2018

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in modern society. Obesity, genetic variations and sex can play a role in determining the severity of the disease. Only a small fraction of genes accounting for NAFLD have been identified and etiology is largely unknown in the two sexes. There is no established therapy for NAFLD and knowledge is limited about the lipotoxic effects of different hepatic lipid species. I intend to examine the contribution of host genetics and sex hormones on diet-induced NAFLD and study the underlying molecular mechanisms in both sexes. I also intend to determine the lipotoxic effects of different hepatic lipid species using systems genetics. To identify novel genes related to the phenotype of interest, we have developed a high resolution mapping tool in mice: The Hybrid Mouse Diversity Panel (HMDP) including ~100 inbred strains of both sexes for which there is dense genotypic information. We study the genetic effects of diet-induced hepatic steatosis by feeding 8 weeks old HMDP mice a high-fat/high-sucrose diet for 8 weeks. We will measure hepatic lipids using a lipidomics approach and perform genome-wide association studies to identify genetic regions modulating the trait. Candidate genes will be validated in cell culture and in vivo mouse studies. To define the impact of sex hormones on hepatic lipids we will utilize samples collected from a study on male and female mice, which have undergone gonadectomy. Our preliminary genetic screen using HMDP unraveled a genome wide significant locus on chromosome 7 associated with hepatic TG accumulation in males. We also have data showing a strong protective effect of estrogen against adiposity as well as insulin resistance. More knowledge about factors contributing to NAFLD may be used for lifestyle intervention, when designing new drugs, or as diagnostic tools to identify subjects of both sexes at risk of developing this prevalent disease