Studies on lipoprotein metabolism and atherogenesis

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.

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:

* The VLDLR is a strong candidate for mediating VLDL effects on synthesis and secretion of PAI-1 in endothelial cells.

* 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.

* 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.

* 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.

List of scientific papers

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
https://pubmed.ncbi.nlm.nih.gov/10224160

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
https://pubmed.ncbi.nlm.nih.gov/11960750

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]

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]