Lipoproteins, cholesterol homeostasis and cardiac health

Abstract

Cholesterol is an essential substance involved in many functions, such as maintaining cell membranes, manufacturing vitamin D on surface of the skin, producing hormones, and possibly helping cell connections in the brain. When cholesterol levels rise in the blood, they can, however, have dangerous consequences. In particular, cholesterol has generated considerable notoriety for its causative role in atherosclerosis, the leading cause of death in developed countries around the world. Homeostasis of cholesterol is centered on the metabolism of lipoproteins, which mediate transport of the lipid to and from tissues. As a synopsis of the major events and proteins that manage lipoprotein homeostasis, this review contributes to the substantial attention that has recently been directed to this area. Despite intense scrutiny, the majority of phenotypic variation in total cholesterol and related traits eludes explanation by current genetic knowledge. This is somewhat disappointing considering heritability estimates have established these traits as highly genetic. Thus, the continued search for candidate genes, mutations, and mechanisms is vital to our understanding of heart disease at the molecular level. Furthermore, as marker development continues to predict risk of vascular illness, this knowledge has the potential to revolutionize treatment of this leading human disease.

The intake of a high-fat diet and grape seed procyanidins induces gene expression changes in peripheral blood mononuclear cells of hamsters: capturing alterations in lipid and cholesterol metabolisms

“…Thus, hmgcs1, a gene that codes for a key enzyme involved in the synthesis of mevalonate from acetyl-CoA during cholesterol synthesis, and lss, which plays a role in lanosterol synthesis (Horton 2002;Espenshade and Hughes 2007) were slightly down-regulated in PBMCs of both HFD and HFD-GSPE animals. In addition, the gene coding for the LDL receptor, which mediates the cellular uptake of cholesterol from cholesterol-rich LDL, chylomicron remnants and VLDL remnants (IDL) (Daniels et al 2009), was also down-regulated (50 % decrease) in the PBMCs of both groups of dyslipidaemic hamsters. Most interestingly, the mRNA levels of the gene coding for the master regulator of cholesterol homoeostasis, SREBP2 (Horton 2002;Espenshade and Hughes 2007;BengoecheaAlonso and Ericsson 2007), were decreased in the PBMCs of the two groups of hamsters that developed dyslipidaemia, compared with their respective healthy controls.…”

Cholesterol: Biosynthesis, Functional Diversity, Homeostasis and Regulation by Natural Products

“…While effectively maintaining intracellular cholesterol homeostasis, these processes leave excess circulating though the body, leading to atherosclerotic plaque development and subsequent coronary artery disease. Thus, levels of cholesterol and related lipids circulating in plasma are important predictive tools utilized clinically to diagnose the risk of a cardiovascular diseases (Daniels et al, 2009;Ikonen, 2008;Simons and Ikonen, 2000;Singh et al, 2007). Cholesterol is transported in the plasma predominantly as cholesteryl esters associated with lipoproteins and dietary cholesterol is transported from the small intestine to the liver in the form of chylomicrons.…”

Current Issues Regarding Prenatal Diagnosis of Inborn Errors of Cholesterol Biosynthesis

“…LDLR peptide is recycled back to the membrane and LDL particles are released into the lysosomes whose enzymes degradate the lipoproteine into amino acids and lipid components. Cholesteryl esters are hydrolyzed by lysosomal acid lipase (LAL) 7 to free cholesterol [Daniels et al, 2009;Jeon & Blacklow, 2005]. Therefore cholesterol can be reesterified by ACAT (a membrane-bound enzyme residing in the ER) and stored as lipid droplets [Zhang et al, 2003;Liu et al, 2005].…”

“…Additionally, microsomal triglyceride transfer protein (MTP) 5 binds the precursor peptide and joins some triglycerides, phospholipids, and cholesteryl esters, allowing ApoB-100 to fold around a small lipid core. Then a higher amount of triglycerides are transferred into the precursor VLDL particle, and it sorts to the Golgi apparatus where additional lipids are recruited in order to form the mature VLDL lipoprotein [Daniels et al, 2009]. Finally VLDLs enter in circulation and distribute free fatty acids to muscle and adipose tissues expressing LPL and become intermediary density lipopoteins (IDLs) that can either be removed from circulation by the liver or they can lose further free fatty acids becoming low density lipoproteins (LDLs) which are important cholesterol transporters [Daniels et al, 2009].…”

“…Then a higher amount of triglycerides are transferred into the precursor VLDL particle, and it sorts to the Golgi apparatus where additional lipids are recruited in order to form the mature VLDL lipoprotein [Daniels et al, 2009]. Finally VLDLs enter in circulation and distribute free fatty acids to muscle and adipose tissues expressing LPL and become intermediary density lipopoteins (IDLs) that can either be removed from circulation by the liver or they can lose further free fatty acids becoming low density lipoproteins (LDLs) which are important cholesterol transporters [Daniels et al, 2009]. Therefore, low density lipoprotein receptor (LDLR) 6 , a transmembrane glicoprotein responsible for uptake of cholesterol-carrying lipoproteins from blood circulation, binds lipoprotein particles at the cell surface, which are internalized by endocytosis and later in the low-pH environment of the endosome, acid-induced dissociation of ligand and receptor occurs.…”