The objectives of this thesis were to elucidate the pathogenesis of metabolic heart disease, evaluate the associated changes in myocardial structure and contractile function, and determine the long... Show moreThe objectives of this thesis were to elucidate the pathogenesis of metabolic heart disease, evaluate the associated changes in myocardial structure and contractile function, and determine the long-term prognostic implications of subclinical myocardial dysfunction on all-cause mortality. Show less
The metabolic syndrome is an increasing problem in our Western society. Many of the features of the metabolic syndrome, like obesity, insulin resistance, dyslipidemia, and hepatic steatosis are... Show moreThe metabolic syndrome is an increasing problem in our Western society. Many of the features of the metabolic syndrome, like obesity, insulin resistance, dyslipidemia, and hepatic steatosis are established risk factors for cardiovascular disease. Growing evidence supports the important role of body free fatty acid handling and/or body distribution of triglycerides in the pathogenesis of the metabolic syndrome-associated problems. We used several different approaches to study the development of obesity, insulin resistance, dyslipidemia, and liver steatosis. In chapter 2 we found that absence of apoC3, a natural LPL inhibitor, enhances FA uptake from plasma triglycerides in adipose tissue leading to increased susceptibility to diet-induced obesity, followed by more severe development of insulin resistance. Therefore, we have shown that regulation of body distribution of triglycerides, in a LPL-dependent process, plays an important role in obesity development. In chapter 3 we found that acute inhibition of the β-oxidation of FA indeed increases hepatic lipid content, but neither stimulates hepatic VLDL secretion nor reduces insulin sensitivity. In chapter 4 we showed that the combination of proteomics with relevant physiological parameters in a sensitive animal model, is a powerful tool, which will aid in identifying workingmechanisms of various dietary FA. In chapter 5 we found that sphingolipids protect the liver from fat and cholesterol-induced steatosis. Since sphingolipids are nutritional compounds present in several daily foods, such as milk and meat, addition of sphingolipids to the diet may decrease traditional cardiovascular risk factors, such as plasma cholesterol and triglycerides. Show less
