Team Ewa Ehrenborg
N-terminal β-barrel motif of the microsomal triglyceride transfer protein. The site of the missense polymorphism Ile128Thr affects the microsomal triglyceride transfer protein (MTTP) functionality. The polymorphic site at Ile128 is marked with red spheres
Functional genetic studies of regulators involved in cardiovascular metabolic diseases
Our group focuses on genes that are important regulators of lipid metabolism in cells. Any constitutive or induced alterations in the expression or function of these genes are likely to have an effect on the lipid accumulation in different tissues and cell types and are thus important determinants of cardiovascular metabolic diseases. Studies ranging from detailed cell and molecular biology to clinical epidemiological investigations of humans are used to characterize the function of the system. A better understanding of the consequences of the genetic regulation is likely to provide new therapeutic approaches to reduce cardiovascular metabolic diseases.
Major research focus
Cardiovascular metabolic diseases are characterised by patho-physiological interrelationships between inflammation and metabolic dysfunction (e.g. insulin resistance and dyslipidemia). Cardiovascular metabolic diseases include disorders such as myocardial infarction, atherosclerosis, cardiomyopathies and heart failure that constitute a leading cause of morbidity and mortality in the Western world. Metabolic disorders including insulin resistance and dyslipidemia contribute to an increased production of risk factors from the fatty liver i.e. glucose, VLDL, haemostatic factors and C-reactive protein. Indeed, liver fat content has been shown to be a novel independent indicator of myocardial insulin resistance and reduced coronary functional capacity. Thus, hemodynamic and metabolic disturbances associated with fatty liver may predispose to CVD. Also macrophages play crucial roles in the progression of atherosclerosis by inducing local inflammatory response through production of cytokines and by uptake of modified lipoproteins, which results in foam cell formation. These cardiovascular metabolic diseases are polygenic diseases strongly influenced by environmental factors and for the vast majority of patients the most plausible background is likely to derive from an adverse combination of unfavourable genotypes on which over-nutrition, lack of physical exercise, obesity and smoking have taken their toll and precipitated the phenotype. The aim is to elucidate the role of key proteins/factors involved in the development of the cardiovascular metabolic diseases using a genetic approach. The studies ranges from clinical epidemiological investigations of humans and physiological examinations based on "recruit-by-genotype" including analyses of tissue biopsies to detailed cell and molecular biology studies. Our group focuses on genes that are important regulators of lipid metabolism in cells. The genes that are of particular interest are the microsomal triglyceride transfer protein (MTTP), peroxisome proliferator activated receptor delta (PPARD) and lipid associated proteins. 1. Phenotypic effects of single nucleotide polymorphisms (SNPs) are studied in relation to cardiovascular metabolic diseases by association studies using metabolic well-characterized cohorts. 2. Putative functional polymorphisms are characterized in detail in vitro by transient transfection assays using reporter constructs in order to measure changes in promoter activity. Protein:DNA interactions are analysed using electromobility shift assays and chromatin immunoprecipitation assays. Stably transfected cell lines are used to study changes in lipid handling and production of inflammatory factors. 3. In vivo effects of genetic variants are studied in macrophages and tissue biopsies from individuals that are recruited by genotype. The allele specific expression of the SNP is analysed in relation to lipid accumulation using TaqMan and Pyrosequencing assays. 4. The regulation of gene expression by microRNAs and splicing are studied in detail in vitro and in tissue biopsies in relation to cardiovascular metabolic diseases by TaqMan assays, transient transfection analyses using reporter constructs and transriptomics
We have significant collaborations with the Center for Cardiovascular and Metabolic Research (CMR), University of Gothenburg (Professor Jan Borén) and with associate professor Anders Gabrielsen, experimental cardiovascular research unit, KI.
Ewa Ehrenborg MD, PhD, Professor, Team Leader
Olivera Werngren Laboratory Assistant
Peter Gustafsson PhD student