Cholesterol - A basic review

Cholesterols are fundamental molecules for animals. Belonging to sterols class, these organic molecules take role on the composition of cell membranes, maintaining fluidity and integrity. Raised serum levels are highly associated with increased risk of stroke and heart disease. The World Health Organization points that one third of ischaemic heart disease can be attributed to high cholesterol (HC). The concern about treatment and prevention of HC and its consequences is global, once it is present in both developing and developed word as a risk factor for other health complications.

The average amount of deaths in the world due to cardiovascular diseases.

Functions:

Precursor to bile acids, steroid hormones in mammals, vitamin D;

Component of cell membranes, maintaining membranes fluidity and permeability: cholesterol molecules interact with fatty acyl chains of phospholipids to increase packing density, produce condensing effect, reduce permeability and maintain membrane fluidity;

Covalent link to proteins.

Gateway

Intestinal Absorption of Cholesterol

Intestinal absorption of cholesterol is a key regulatory in human sterol metabolism because it determines what percentage of cholesterol produced by liver and what percentage of dietary cholesterol is released into the blood. In normal metabolism, approximately 55% of the intestinal absorption enters the blood through the enterocyte per day. Also, there is a mechanism to remove the excess of cholesterol from the enterocyte. This process are made by ATP-binding cassette (ABC) protein family, ABC1, ABCG5 and ABCG8. These proteins transport excessive cholesterol from enterocyte back into the gut. Then, cholesterol is eliminated in the faeces as unreabsorbed sterols and bile acids.

Cholesterol Synthesis

Biosynthetic pathway

The first stage of cholesterol synthesis is the production of mevalonate, which is the rate-limiting step in cholesterol formation. In this pathway, two molecules of acetyl-CoA condense forming acetoacetyl-CoA which then condenses with a third molecule of acetyl-Coa forming β-hydroxy-β-methylglutaryl-CoA (HMG-CoA). Then, HMG-CoA is reduced to mevalonate catalyzed by HMG-CoA reductase. The regulation of the activity of HMG-CoA reductase is controlled by:

Transcriptional Control: the rate of synthesis of HMG-CoA reductase mRNA is controlled by sterol-regulatory element-binding proteins (SREPBs);

Proteolytic Degradation of HMG-CoA reductase: high levels of cholesterol and bile salts can lead to enzyme proteolysis;

Regulation by covalent modification: the activity of the reductase is also regulated by phosphorylation and dephosphorylation of the HMG-CoA reductase.

The second stage is the conversion of mevalonate to two activated isoprenes. Three phosphate groups are transferred from ATP molecules to mevalonate, forming isopentenylpyrophosphate and dimethylallyl pyrophosphate. The next stage is the reactions between isoprenes forming squalene containing 30 carbons. In the last stage, the enzyme squalene monooxygenase adds one atom of oxygen to the squalene molecule forming an epoxide and NAPH reduces the other oxygen atom to H2O. Then, it allows the conversion in a cyclic structure leading to formation of lanosterol and finally, cholesterol.