Studies on lipoprotein metabolism and atherogenesis

<p>Atherosclerosis is the primary cause of cardiovascular events such as angina pectoris and myocardial infarction, which together with stroke are responsible for around 50% of all deaths in the United States and Europe. Usually atherosclerosis develops over several decades and leads to a progressive narrowing of arterial vessels. Hypercholesterolemia is an established driving force. Therapeutic alternatives are available, but still not all patients reach their treatment goals. Therefore there is still a need for new strategies to optimize plasma cholesterol levels and reduce the development of atherosclerosis.</p><p>This study aims: to explore basic components involved in the metabolism of atherogenic lipoproteins such as the very low-density lipoprotein receptor and to explore potential new approaches to reduce atherosclerosis. From our studies the following conclusions could be drawn:</p><p>* The VLDLR is a strong candidate for mediating VLDL effects on synthesis and secretion of PAI-1 in endothelial cells.</p><p>* The VLDLR is up-regulated in 3T3-L1 cells during the differentiation into an adipocytelike phenotype, a process mediated by dexamethasone in a time and dose dependent manner, which involves a functional glucocorticoid receptor. It is not obligatory associated with the development of an adipocyte-like phenotype.</p><p>* Cholic Acid (CA) is an important player for the development of atherosclerosis since in mice, absence of CA reduces the atherosclerotic lesion area with approximately 50%. The atheroprotective effect does not seem to be mediated by FXR, but rather due to the absence of CA-dependent micelles in the intestine, reducing the cholesterol uptake.</p><p>* GC-1, a thyroid hormone receptor β-modulator, reduces atherosclerosis development in ApoE KO animals. This could be explained by a decrease in ApoB-containing lipoproteins in serum, perhaps secondary to an increased clearance via the LDLR upregulation and an increased BA synthesis in the liver.</p><h3>List of scientific papers</h3><p>I. Nilsson L, Gåfvels M, Musakka L, Ensler K, Strickland DK, Angelin B, Hamsten A, Eriksson P (1999). VLDL activation of plasminogen activator inhibitor-1 (PAI-1) expression: involvement of the VLDL receptor. J Lipid Res. 40(5): 913-9 <br><a href="https://pubmed.ncbi.nlm.nih.gov/10224160">https://pubmed.ncbi.nlm.nih.gov/10224160</a><br><br></p><p>II. Ensler K, Mohammadieh M, Bröijersén A, Angelin B, Gåfvels M (2002). Dexamethasone stimulates very low density lipoprotein (VLDL) receptor gene expression in differentiating 3T3-L1 cells. Biochim Biophys Acta. 1581(1-2): 36-48 <br><a href="https://pubmed.ncbi.nlm.nih.gov/11960750">https://pubmed.ncbi.nlm.nih.gov/11960750</a><br><br></p><p>III. Slätis K, Gåfvels M, Kannisto K, Ovchinnikova O, Paulsson-Berne G, Parini P, Jiang Z-Y, Eggertsen G (2009). Cholate depletion: a new approach to reduce atherosclerotic development. [Manuscript]</p><p>IV. Slätis K, Kannisto K, Gåfvels M, Eggertsen G, Rehnmark S, Baxter J, Webb P, Parini P (2009). Reduction of atherosclerosis in ApoE deficient mice by GC-1. [Manuscript]</p>