Cholestrol Flashcards
What is cholesterol?
Cholesterol is a steroid composed of 27 carbon atoms. It can be seen to be composed of cyclic rings with a hydrophobic tail. The steroid ring structure is planar. Apart from the hydroxyl group at position 3, the molecule is very hydrophobic, consisting only of carbon and hydrogen atoms.
What is cholesterol’s main function?
Cholesterol is a vital component of cell membranes, and more than 90% of the cholesterol in our bodies is found in cell membranes. A key property of cholesterol is that it can increase and decrease membrane stiffness, depending on the temperature and the nature of the membrane. Given the great need for cholesterol as a membrane component, all physiological requirements for cholesterol are supplied by the liver through de novo synthesis of cholesterol from acetyl-CoA.
What are the parts of the cholesterol synthesis pathway?
- Synthesis of isopentenyl pyrophosphate, an activated isoprene unit which serves as a key building block (cytoplasm).
- Condensation of six molecules of isopentenyl pyrophosphate to form squalene (cytoplasmic reactions).
- Cyclisation and demethylation of squalene by monooxygenases to give cholesterol (ER reactions).
Describe step 1 of cholesterol synthesis
These reactions occur in the cytoplasm. First, two molecules of acetyl CoA condense to form the four carbon species Acetoacyl CoA. Next, another molecule of acetyl-CoA condenses to form 3-hydroxy-3-methyl glutaryl-CoA (HMG-CoA). In the next reaction, HMG-CoA reductase reduces HMG-CoA to give the molecule mevalonate. HMG-CoA reductase is under intense negative feedback control by the end product of the pathway, cholesterol, the reaction product mevalonate and also bile salts. Mevalonate then undergoes sequential phosphorylation at the hydroxyl groups at position 3 and 5, followed by decarboxylation to form 3-Isopentenyl pyrophosphate (isopentyl PP) which is 5 carbon.
Describe step 2 of cholesterol synthesis
Take place in the cytoplasm. Firstly, via an isomerization reaction Dimethylallyl pyrophosphate is produced from isopentyl PP. Two condensation reactions which isopentyl PP is sequentially added to the Dimethylallyl pyrophosphate grows the chain to the 15 carbon species Farnesyl pyrophosphate. Two farnesyl-PP molecules then condense to form the 30 carbon molecule squalene plus 2 molecules of pyrophosphate
Describe step 3 of cholesterol synthesis
These reactions take place in the ER. Firstly, squalene is reduced in the presence of oxygen and NADPH to form squalene epoxide which has a different C=C bond distribution, priming the molecule for carbon ring fusion (Step 1). Secondly, the enzyme squalene epoxide lanosterol-cyclase catalyses the formation of Lanosterol (Step 2). A series of 1,2-methyl group and hydride shifts along the chain of the squalene molecule result in the formation of the four rings. Lanosterol is subsequently reduced and three methyl units removed (demethylated) to generate cholesterol. This takes place via 19 discrete steps which have been omitted
How are bile salts synthesised from cholesterol?
Bile salts are the major breakdown products of cholesterol and account for about half of the 800 mg of cholesterol made each day by the liver. Cholesterol can be converted by a series of reactions into the primary bile salt glycocholate and also taurocholate.
How are steroid hormones synthesised from cholesterol?
The precursor pregnenolone is generated from cholesterol by the action of the enzyme desmolase. All five classes of steroid hormones come from pregnenolone: Progestagens, glucocorticoids, mineralocorticoids, androgens and oestrogens.
How is vitamin D synthesised from cholesterol?
Vitamin D is a collective term for a group of steroids which are vital for the intestinal absorption of important ions needed for bone development, namely calcium, phosphate and magnesium. The bulk of the Western diet is low in vitamin D and our main source is from the activity of UV light upon 7-dehydrocholesterol in the epidermis of the skin
What causes rickets?
Calcitriol is the most active vitamin D metabolite and plays a key role in calcium metabolism. It functions as a steroid hormone, binding to vitamin D response elements (VDREs) in the promoter of target genes and inducing key genes involved in bone metabolism. A deficient of Vitamin D3 in childhood leads to rickets, a defect of bone development in children.
What is hypercholestraemia?
Familial hypercholesterolaemia (FH) is a monogenic dominant trait in which cholesterol transportation is defective. Individuals who carry a single copy of a mutant gene (heterozygotes) have cholesterol levels approximately 2-3 times higher than in normal people and are susceptible to atherosclerosis (hardening of the arteries) in middle age. Homozygotes who carry two copies of a mutant gene are severely affected. Their serum cholesterol levels are five times higher than in healthy individuals and severe atherosclerosis and coronary infarction may be observed in adolescence.
What is the disease mechanism underlying familial hypercholestraemia?
Cholesterol in the form of LDL was taken up by a specific receptor molecules on the cell surface - the LDL receptor (LDLR). Mutations in several domains of the LDL receptor lead to FH. Over 1000 mutations reported affecting either receptor expression, LDL binding or LDLR endocytosis and recycling, all of which can manifest in FH.
How is hypercholestraemia controlled?
In terms of controlling hypercholesterolaemia , there are two main strategies. Inhibition of de novo cholesterol synthesis by the liver, or the reduction of dietary cholesterol absorption by the intestines. This is achieved by HMG-CoA reductase inhibitors and resins respectively.
How do resins work?
These bind or sequester bile acid-cholesterol complexes preventing their reabsorption by the intestine. They can lower LDL (“bad” cholesterol) by 15 -30% and raise HDL (“good” cholesterol) by 3 - 5%. Examples are Cholestyramine (brand names: Questran, Prevalite).
How do HMG-CoA-Reductase inhibitors work?
Also known as a statins e.g. Lipitor (Pfizer), Crestor (Astra Zeneca). The mechanism of action of the molecule lovastatin is that of a competitive inhibitor of HMG-CoA Reductase.
