Abstract
Elevated plasma cholesterol is a heritable trait and a risk factor for the development of cardiovascular disease. Although several major biochemical pathways regulating cholesterol metabolism have been identified, questions regarding the details of this regulation remain. In fact, common genetic polymorphisms in candidate genes explain only 5 to 7% of variation in high- and low-density lipoprotein cholesterol levels between individuals. This suggests that many of the factors influencing cholesterol metabolism, and potentially the etiology of cardiovascular disease, are unknown. Here, we review recent functional genomic research that, combined with results from genome-wide association studies, provides a powerful tool to identify novel candidate genes relevant to cholesterol metabolism.
Highlights
Cholesterol is an integral component of lipid membranes in eukaryotic cells that is required for maintaining membrane fluidity and facilitating the trafficking and signaling of membrane-associated proteins
The receptor-ligand complex is subsequently absorbed into the cell through clathrinmediated endocytosis, and cholesterol is used by a variety of downstream biochemical pathways
In this third pathway, circulating high-density lipoprotein (HDL) acts as the primary acceptor of cholesterol from non-liver cells. These pathways involve a network of many trans cription factors, binding proteins, enzymes and receptors. Alterations in these pathways that lead to elevated plasma cholesterol levels correlate strongly with increased risk of cardiovascular disease (CVD) [2]
Summary
Cholesterol is an integral component of lipid membranes in eukaryotic cells that is required for maintaining membrane fluidity and facilitating the trafficking and signaling of membrane-associated proteins. Cholesterol is synthesized when intra cellular levels are low, through activation of the SCAP/ SREBP signaling cascade. A reverse cholesterol transport pathway is activated when the cell accumulates excess cholesterol, which must be transported to the liver for excretion into the bile In this third pathway, circulating high-density lipoprotein (HDL) acts as the primary acceptor of cholesterol from non-liver cells. Together, these pathways involve a network of many trans cription factors, binding proteins, enzymes and receptors. These pathways involve a network of many trans cription factors, binding proteins, enzymes and receptors Alterations in these pathways that lead to elevated plasma cholesterol levels correlate strongly with increased risk of cardiovascular disease (CVD) [2]. Familial hypercholesterolemia, which is caused by mutations in the low density lipoprotein receptor (LDLR) gene, leads to a reduced number of functional LDL receptors and results in the severe elevation of plasma LDL cholesterol levels [3]
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