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• W2111177371 abstract "The leading cause of death in the Western world continues to be coronary heart disease (CHD). At the root of the disease process is dyslipidemia – an aberration in the relevant amounts of circulating blood lipids. Cholesterol builds up in the arterial wall and following rupture of these plaques, myocardial infarction or stroke can occur. Heart disease runs in families and a number of hereditary forms are known. The leading cause of adult dyslipidemia presently however is overweight and obesity. This thesis work presents an investigation of the molecular genetics of common, hereditary dyslipidemia and the tightly related condition of obesity. Familial combined hyperlipidemia (FCHL) is the most common hereditary dyslipidemia in man with an estimated population prevalence of 1-6%. This complex disease is characterized by elevated levels of serum total cholesterol, triglycerides or both and is observed in about 20% of individuals with premature CHD. Our group identified the disease to be associated with genetic variation in the USF1 transcription factor gene. USF1 has a key role in regulating other genes that control lipid and glucose metabolism as well as the inflammatory response – all central processes in the progression of atherosclerosis and CHD. The first two works of this thesis aimed at understanding how these USF1 variants result in increased disease risk. Among the many, non-coding single-nucleotide polymorphisms (SNPs) that associated with the disease, one was found to have a functional effect. The riskenhancing allele of this SNP seems to eradicate the ability of the important hormone insulin to induce the expression of USF1 in peripheral tissues. The resultant changes in the expression of numerous USF1 target genes over time probably enhance and accelerate the atherogenic processes. High-density lipoprotein (HDL) is responsible for the transport of excess cholesterol from peripheral tissues to the liver for excretion in bile. This process is termed the reverse transport of cholesterol. An inverse correlation exists between the levels of HDL-C and the risk for CHD. High levels of HDL-C protect against atherosclerosis and this protection is decreased in patients with low HDL-C levels. The ABCA1 cholesterol transporter is instrumental in the initial transfer of cholesterol from cells to the nascent HDL particle for transport to the liver. In the third work of this thesis we investigated the early steps of the reverse transport of cholesterol in Finnish families with familial low-HDL-C to determine whether a defect there was involved in the increased risk in these families for developing CHD. The role of ABCA1, critical to this process, was investigated in patients as well as healthy control subjects. Patients with low-HDL-C were found to carry rarer DNA variants (SNPs) significantly more often than healthy subjects and sets of these SNPs were related dose-dependently to HDL-C levels. While patient-derived macrophages were only marginally poorer at the efflux of cholesterol, they exhibited significantly higher ABCA1 expression levels. It follows, that the cholesterol efflux capability of patient-derived cells in proportion to the ABCA1 expression was markedly lower. These results suggest that genetic variation within the ABCA1 gene and defective function of the protein are potential contributors to the impaired RCT process in Finnish families with low-HDL-C. Dyslipidemias often represent an outcome of obesity and in the final work of this thesis we wanted to address the metabolic pathways related to acquired obesity. It is recognized that active processes in adipose tissue play an important role in the development of dyslipidemia, insulin resistance and other pathological conditions associated with obesity. To minimize the confounding effects of genetic differences present in most human studies, we investigated a rare collection of identical twins that differed significantly in the amount of body fat. In the obese, but otherwise healthy young adults, several notable changes were observed. In addition to chronic inflammation, the adipose tissue of the obese co-twins was characterized by a marked (47%) decrease in amount of mitochondrial DNA (mtDNA) – a change associated with mitochondrial dysfunction. The catabolism of branched chain amino acids (BCAAs) was identified as the most down-regulated process in the obese cotwins. A concordant increase in the serum level of these insulin secretagogues was identified. This hyperaminoacidemia may provide the feed-back signal from insulin resistant adipose tissue to the pancreas to ensure an appropriately augmented secretory response. The down regulation of BCAA catabolism correlated closely with liver fat accumulation and insulin. The single most up-regulated gene (5.9 fold) in the obese co-twins was osteopontin (SPP1) – a cytokine involved in macrophage recruitment to adipose tissue. SPP1 is here implicated as an important player in the development of insulin resistance. These studies of exceptional study samples provide better understanding of the underlying pathology in common dyslipidemias and other obesity associated diseases –important for future improvement of intervention strategies and treatments to combat atherosclerosis and coronary heart disease." @default.
• W2111177371 created "2016-06-24" @default.
• W2111177371 creator A5002864290 @default.
• W2111177371 date "2008-03-14" @default.
• W2111177371 modified "2023-09-28" @default.
• W2111177371 title "Molecular Background of Common Dyslipidemias" @default.
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