Cholesterol Biosynthesis and drug treatment for high cholesterol

Hyperlipidemia, High cholesterol treatment.

For high cholesterol treatment  it is important to understand the underlying root cause of the increased cholesterol level. There are following two types of hyperlipidemia.

1. Primary (familial) hyperlipidemia. FH

2. Secondary (acquired) hyperlipidemia.

Familial hyperlipidemia is a genetic disorder caused by mutations in genes LDLR, APOB, and PCSK9 genes which are responsible for production of proteins which removes the LDL VLDL from the bloodstream. In FH the cholesterol level is always at a higher side increasing the risk of coronary artery disease CAD, atherosclerosis, chest pain, angina, myocardial infarction and sudden death. FH is detected in early childhood,

Secondary or acquired hyperlipidemia:

It occurs due to other underlying metabolic defects and lifestyle, like diabetes, poor food habits. High Cholesterol occurs in adults due to lifestyle, rarely some patients are seen with low cholesterol at younger age.

Lack of physical movement, lack of exercise cause defective fat metabolism, that keeps LDL VLDL levels on higher side, increasing the risk of deposition of cholesterol in the blood arteries and veins.

Pathophysiology of Hyperlipidemia

Low density and very low density lipoproteins upon increase in blood concentration try to crystallize and solidify over the surfaces of blood vessels, causing deposition of plaques of cholesterol.

Due to the deposition of cholesterol, damage to endothelial cells occurs, this is the process of atherosclerosis. The damaged blood vessels develop inflammation and often triggers the autoimmune response against the body’s own body blood vessels and its tissues and ischemia of heart blood vessels.

Causes for Acquired hyperlipidemia and high cholesterol treatment.

Drug induced hyperlipidemia: amiodarone, glucocorticoids, causes increase in cholesterol.

Endocrine system:

Hypothyroidism, diabetes.

Untreated hypothyroidism and diabetes leads to Secondary (acquired) hyperlipidemia.

Lifestyle and food habits:

Smoking and chewing tobacco, alcohol, damages liver and pancreas, triggers autoimmune diseases, due to which damage to pancreas and liver is observed.

Treatment for Hyperlipidemia:

1.Quite smoking

2. Regular physical exercise.

3. Diet control: Eat food that consists of low fat.

4. Anti cholesterolemia medicines.

Treatment of high cholesterol (hypercholesterolemia)

Total cholesterol is measured as the sum of LDL HDL and triglycerides.

1. High density lipoproteins:  The density that is molecular weight of the lipoprotein is high, compared to LDL, HDL absorbs the LDL and transport it in to liver where it is used for biosynthesis of bile salt and vitamin D and for stored as fat in to body cells.

Which makes sure that the harmful LDL concentration is kept at the lower side so that it does not settle over the inner walls of the arteries.

Ideal level of HDL is 40 to 50 mg/DL

2. Low density lipoproteins: The Low density lipoprotein is also called as Bad cholesterol, it is called bad cholesterol because this is the one which forms blocks in the blood vessels, and it is responsible for developing atherosclerosis and Coronary artery disease CAD, Cardiac coronary diseases CCD. Cardiovascular diseases CVD

After deposition of cholesterol in the arteries, the immune system is activated against these defective arteries and it causes autoimmune disease.

Sudden death occurs in the cases where LDL is higher and left untreated.

The Ideal level of LDL is 100 mg /DL

3. Triglycerides: Triglycerides are nothing but the oil that we consume in food, it is absorbed from food and this keeps on circulating throughout the body until it is metabolized and converted into glycogen or fat.

This helps to increase the level of LDL therefore the level of triglycerides is also important to maintain a low level.

The Ideal triglyceride level is 150 mg/DL.

Total cholesterol:

Total cholesterol is the sum of all above three lipoproteins LDL, HDL and triglycerides therefore the optimum total cholesterol is 50+100+150 = 200 mg/DL.

Therefore, a total cholesterol level below 200 mg/DL is desired to maintain good health and avoid atherosclerosis and Coronary artery disease CAD, Cardiac coronary diseases CCD. Cardiovascular diseases CVD.

Care must be taken to take into account the LDL level in even the total cholesterol is beyond 200 mg/DL. LDL should be below 100 mg/DL. Triglyceride and HDL level increase can be managed with diet control and exercise. While the LDL level should be treated with anticholesterolemic drugs and treating underlying causes like side effects of drugs like protease inhibitors in HIV treatment.

Drug induced hypercholesterolemia:

1) Selective serotonin reuptake inhibitors (SSRIs):

2) Beta blocker drugs increase cholesterol level: propranolol, atenolol and metoprolol

3) Protease Inhibitors: in HART AVR treatment for HIV.

4) Diuretics: Thiazide and loop diuretics increase Total cholesterol by increasing triglyceride, and (LDL) do not change (HDL) increase in triglyceride is observed with β-Adrenergic antagonists. With α-Adrenergic antagonists the reduction in triglyceride level is observed, while HDL is elevated VLDL and LDL cholesterol is reduced.

5) Prednisolone.

6) Anabolic steroids.

7) Birth control pill containing Progestin.

8) Retinoid: Used to treat acne, person taking vitamin A supplement may have increased LDL level.

Disease that cause increase in cholesterol, and the treatment for high cholesterol.


Due to decreased catabolism and decreased LDL-receptors’ activity there is increase in the total cholesterol and LDL in hypothyroidism.

2) Chronic kidney disease: CKD causes decreased secretion of lipoprotein lipase and causes decrease in catabolism of lipid and LDL-receptor activity, which causes increased triglycerides.

3) Diabetes: Glucose is not only metabolized in glycogen but also its one of origin for lipid biosynthesis (lipogenesis) thus causing increased lipid levels.

4) HIV AIDS : HART AVR drugs used to treat HIV AIDS caused hyperlipidemia.

5) Liver disease: Cholesterol is metabolized in the liver, chronic liver disease and liver disease cause increase in cholesterol levels.

6) Hepatitis: Causes liver damage hence also causes increase in cholesterol.

Anticholesterolemic drugs, Medicines for lowering high cholesterol.

Medicines for treatment of high cholesterol.

Statins: Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin

Fibrates: Fenofibrate, Gemfibrozil

Niacin: Effect as anticholesterolemic agent is comparable with statins but drug Niacin causes liver damage therefore it should be used with caution.

Lipid absorption inhibitors: Ezetimibe

Bempedoic acid: do not cause muscle pain as in case of statin.

Combination of Bempedoic acid and Ezetimibe.

Bile-acid-binding resins: Cholestyramine, colesevelam, colestipol.

PCSK9 inhibitors: Alirocumab, Evolocumab

Omega-3 fatty acid supplements:

Mode of action and Side effects and contraindications of Anticholesterolemic drugs, Medicines for lowering high cholesterol.

Cholesterol Biosynthesis and drug treatment for high cholesterol
Cholesterol Biosynthesis and drug used to treat for high cholesterol


Statins mode of action as cholesterol lowering drugs:

For understanding how anticholesterolemic drugs work it’s important to understand the biosynthesis of cholesterol it occurs through the lanosterol pathway. It consists of 12 enzyme systems that convert acetyl coenzyme A to cholesterol through the lanosterol pathway, cholesterol is biosynthesized from acetyl coenzyme A through a number of biochemical reactions.

One of such important biosynthesis reactions is conversion of 3- hydroxy3-methylglutaryl-CoA (HMG-CoA) to Mevalonic acid reaction that is catalyzed by enzyme HMG-CoA reductase.

Statin groups of drugs block the enzyme HMG-CoA reductase. This is achieved by stereochemical orientation of statins comparable with 3- hydroxy3-methylglutaryl-CoA statins taken up by HMG-CoA reductase competitive inhibition of HMG-CoA reductase is achieved.

Which further stops the biosynthesis of cholesterol.

Side effects of statin drugs:

Statin drugs are associated with muscle pain, prolonged use may cause myopathy, dose of 80 mg and high causes rhabdomyolysis.

The risk and benefit factors should be considered during the treatment.


Fibrate class of drug activates metabolism of triglycerides and HDL moves them to liver for storage. Thereby reducing total cholesterol. The drug fibrates act by activation of peroxisome proliferator activated receptor (PPAR) alpha which control the metabolism of Triglycerides (TG) and HDL

Contraindication of fibrates:

Risk of rhabdomyolysis increases in combination of fibrates (gemfibrozil) with statins, therefore this combination of fibrate (gemfibrozil) and statins is contraindicated.


Niacin causes noncompetitive inhibition of hepatocyte diacylglycerol acyltransferase-2, an important enzyme for TG synthesis. and decrease total cholesterol.

Effect as an anticholesterolemic agent is comparable with statins but the drug Niacin causes liver damage therefore it should be used with caution.

Lipid absorption inhibitors:


Ezetimibe causes reduced absorption of cholesterol from the small intestine, and indirectly reduces the total cholesterol, Ezetimibe is prescribed in high cholesterol along with a statin drug.

Contraindications for Ezetimibe:

1) Earlier history of allergic reaction to Ezetimibe

2) Angioedema

3) Liver diseases.

Bempedoic acid:

Mode of action of Bempedoic acid:

Bempedoic acid is a prodrug it is converted to thioester along with coenzyme A, and inhibit the enzyme Adenosine triphosphate-citrate lyase (ATP citrate lyase) in the biosynthesis of cholesterol in lanosterol pathway. Bempedoic acid does not cause muscle pain as in the case of statin.

Bile-acid-binding resins Sequestrants:

Cholestyramine, colesevelam, colestipol.

These are cation resins which are positively charged molecules, when they come in contact with bile acid which has negative charge over it, sequestering resin binds with bile acid and prevents the absorption of lipid from the intestine. Thus Bile-acid-binding resins Sequestrants reduce total cholesterol.

Side effects of bile acid sequestrant :

Reduced absorption of vitamins from intestine and interaction with other drugs and hormones in event of concomitant administration through oral route.

Contraindication of Bile-acid-binding resins Sequestrants:

Hepatitis, Liver diseases, serum aminotransferase and alkaline phosphatase elevations is observed which diminishes with discontinuation of the drug Bile-acid-binding resins Sequestrants.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors:

Alirocumab, Evolocumab

The US FDA has approved drugs Alirocumab, Evolocumab in 2015, as anti-cholesterol medicines. PCSK9 enzyme inhibitors. PCSK9 acts up on a receptor for low-density lipoprotein and causes degradation, increasing the concentration of circulating (LDL). PCSK9 enzyme inhibitors inhibit enzymes and the apparent lowering of cholesterol is achieved.

Omega-3 fatty acid supplements:

Omega-3 fatty acid causes increased level of lipoprotein lipase as a positive feedback mechanism and thus causes decreased triglyceride and HDL and LDL levels. Owing to double bond at omega position on fatty chain they are good source for neutralization of free radicals and their harmful effect on the body like autoimmune diseases liver diseases.

Omega-3 fatty acids protect body cells from the harmful effect of oxidizing free radicals.

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