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Cholesterol is an essential component of cell membranes, precursor steroids, biliary acids and other components of significant importance in live organisms; it is synthesized only by animals through a series of enzymatic pathways and processes and regulated by four distinct mechanisms; feed-back inhibition, control of gene expression, rate of enzyme degradation and phosphorylation-dephosphorylation. Cholesterol begins with acetyl-CoA from mitochondrion which is synthesized through a series of metabolic pathways to cholesterol (as seen in figure 1). Cholesterol is required to build and maintain cell membranes as well as the proper functioning of the nervous system. The cholesterol referred to when discussing the subject of levels in blood plasma is found as a plasmatic lipoprotein; a complex of a cholesterol and triglyceride core, coated by phospholipids and protein. These lipoproteins are further classified into four categories in relation to their densities; chylomicrons, high-density lipoproteins (HDLs), low-density lipoproteins (LDLs) and very low density lipoproteins (VLPs). The main cause of high cholesterol levels refers to the concentration of LDLs in the blood plasma or commonly referred to as ‘bad cholesterol.' If the concentration of LDLs is high, it signifies a high rate of cholesterol deposition in the arteries. LDLs are regulated through a receptor-mediated endocytosis, Low-density lipoprotein receptors (LDLRs) sit on the outer surface of many types of cells, where they pick up LDLs circulating in the bloodstream, binding to the Apolipoprotein B (Apo-B) which is essential in the conformation and formation of LDLs and acts as a ligand to bind to receptors, and transport them into the cell (Brown and Goldstein 1986). Once inside the cell, the LDL is broken down to release cholesterol for intracellular use. The cholesterol is then used, stored, or removed from the body, LDLRs then exit the cell to the surface in order to bind to other circulating LDLs. Low-density lipoprotein receptors as well as Apo-B, play a critical role in regulating the amount of cholesterol in the blood. They are particularly abundant in the liver, which is the organ responsible for removing most excess cholesterol from the body. The number of low-density lipoprotein receptors on the surface of liver cells determines how quickly cholesterol (in the form of low-density lipoproteins) is removed from the bloodstream.

Familial hypercholesterolemia (FH) is characterized by raised serum LDL cholesterol levels, which result in excess deposition of cholesterol in tissues, leading to accelerated atherosclerosis and increased risk of premature coronary heart disease. FH results from defects in the hepatic uptake and degradation of LDL via the LDL-receptor pathway, commonly caused by a loss-of-function, due to a miss-sense mutation, in the LDL-receptor gene (LDLR) or by a mutation in the gene encoding apolipoprotein B (Apo-B). Mutations in the LDL receptor gene cause the primarily autosomal dominant disease familial hypercholesterolemia (FH) which is prevalent in about 0.2% of the general world population (Goldstein and Brown 1989). Although other cases of mutations (both loss-of-function and gain-of-function) upon a gene that cause FH both directly and indirectly have been documented. The most recent addition to the database of genes in which defects cause FH is an autosomal recessive one encoding a member of the proprotein convertase family, PCSK9. Rare dominant gain-of-function mutation in PCSK9 cosegregate with hypercholesterolemia, and one mutation is associated with a particularly severe FH phenotype. Expression of PCSK9 normally down regulates the LDLR pathway by indirectly causing degradation of LDLR protein, and loss-of-function mutations in PCSK9 result in low plasma LDL levels (Soutar AK, et al). Taken together, these findings indicate that heritable variation in plasma LDL cholesterol is conferred by sequence variation in various loci, with a small number of common and multiple rare gene variants contributing to the phenotype (Burnett JR, et al).
As the common mutation in the LDLR gene which leads to FH is typically inherited through an autosomal dominant matter, the inheritance of only one abnormal gene results in the presence of the disease. The heterozygous form of the disease is much less severe than the homozygous FH; those that have inherited two abnormal genes. Whether the subject is heterozygous or homozygous, along with the environment determines the phenotypic penetrance of the mutation.
Plasmatic cholesterol levels can be lowered by such methods as statins, bile acid sequestrants and other processes. Statins inhibit enzyme HMGCoA reductase, which is a rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis (as seen in figure 1). Inhibition in liver decreases cholesterol synthesis and increases synthesis of LDL, thus lowering LDL levels in blood plasma. Bile acid sequestrants disrupt the circulation of bile acids by sequestering them and preventing their re-absorption into the gut. As bile acids are synthesized from cholesterol, disruption of absorption will decrease cholesterol levels, as less cholesterol will be synthesized through stimulating the feed-back inhibition regulation mechanism. The synthesis of in vivo cholesterol largely depends upon the dietary intake of a person. With the mutation of the LDLR gene, a high cholesterol diet would increase the rate of deposition of cholesterol in the arteries. This is because a large amount of cholesterol is being supplied to a system which is unable to effectively remove or bind to the LDLs, and is not achieving the needed synthesis of cholesterol which is required by the system. Therefore, a diet low in cholesterol would help maintain plasmatic cholesterol levels, and reduce the risk of heart attacks.