Identificador: TDX:635
Autors: Guardiola Guionnet, Montserrat
Resum:
Cardiovascular disease is the main cause of mortality in industrialised countries. Its high prevalence is mainly due to environmental factors (sedentary lifestyle, saturated fat rich diet and tobacco consumption, among others), which together with genetic predisposition could result in increased disease risk. One of the key factors in the development of atherosclerosis are circulating lipids which are guided by the apolipoproteins (APO). The malfunctioning of these proteins due to genetic variants could affect, for example, the concentration and circulating time of lipids. The APOA5 is a key gene modulating triglyceride (TG) metabolism, and our hypothesis is that APOA5 may also modify the circulating levels of other metabolic components highly linked to TG by influencing the synthesis and secretion of TG-rich particles.Using the genetic variability of the APOA5 gene in two populations, healthy men and type 2 diabetic patients, we have described that carriers of the -1131T>C variant present with more than 15% higher TG levels, being this effect mainly due to a greater TG content in circulating VLDL particles. We have also described that this variant affects vitamin E concentrations in both populations, increasing its levels in circulation. Vitamin E is a potent antioxidant, but this variant does not affect the oxidative status of the subjects, because its levels rise in the same proportion than TG do.Since the circulating TG levels can be affected by other factors such as the pharmacological treatment (for example, the protease inhibitors used for the AIDS therapy induce hypertriglyceridemia), we studied the role of APOA5 in a population of patients infected by the VIH virus, and we found that in the group of subjects treated with protease inhibitors, carrying the -1131C variant could increase more than 40% the levels of circulating TG. They also present with increased plasma total cholesterol levels, resulting in the presence of a pro-atherogenic lipid profile.To go deeper in the mechanisms of APOA5 we have used an animal model for atherosclerosis, the APOE-deficient mouse. We had different groups of animals depending on whether they received conventional diet or a saturated fat rich diet supplemented or not with cholesterol. The animals were sacrificed at different ages (16, 24 and 32 weeks). We have demonstrated that the hepatic expression of the APOA5 gene is repressed by dietary saturated fat, reaching a 75% descent. Furthermore, the hepatic expression of APOA5 increases with the age of the animals. We have also published that the expression of APOA5 correlates with the atherosclerotic lesion area and the degree of inflammation in those animals. Till date, it has been published that the gene was only expressed in the liver. The liver is one of the main organs regulating lipid metabolism and is responsible of the synthesis of particles rich in TG from an endogenous origin, but is not the only tissue capable of doing that. The intestine is also involved in the synthesis of TG-rich particles from exogenous origin. We have also demonstrated that APOA5 is not only expressed in the liver in humans, but also in the intestine. For that purpose we used a human intestine cell model (TC-7/ Caco2 cells), and although it is expressed at low levels, we have been able to describe that its intestinal expression is modified by dietary components (long- and short-chain fatty acids) and by hypolipemiant drugs (a PPARα agonist).Conclusion: APOA5 is a key gene modulating circulating TG levels, in dislipemic patients (diabetics or HIV patients under antiretroviral treatment) and even in healthy men, and its expression is affected by dietary components, in the liver and in the intestine, and also by hypolipemiant drugs.
Repositori URV