Question

How does an HMG-CoA reductase inhibitor reduce cholesterol?

Answer 1

Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs

Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, also known as "statins," are used adjunctively to diet and exercise to treat hypercholesterolemia by lowering total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) concentrations while increasing high-density lipoprotein cholesterol (HDL-C) concentrations

Mechanism of Action

Conversion of 3-hydroxy-3-methyl glutaryl-CoA (HMG-CoA) to mevalonate by HMG-CoA reductase in the hepatocytes is the first and rate-limiting step in cholesterol biosynthesis. Statins competitively inhibit HMG-CoA reductase enzyme. Statins bind to the active site of the enzyme and induce a conformational change in its structure, thus reducing its activity. Also, the binding affinity of statins for HMG-CoA reductase is 10000 times higher than the substrate (HMG-CoA) thus preventing the action of the enzyme and reducing the intracellular synthesis of cholesterol

Statins have a significant impact on lowering cholesterol since most of the circulating plasma cholesterol comes from the internal synthesis in hepatocytes rather than the diet

The reduced level of cholesterol in hepatocytes secondary to statin use activates the proteases that cleave membrane-bound sterol regulatory element-binding proteins (SREBP), which further migrate to the nucleus and binds sterol response elements. This binding results in increased transcription of the LDL receptor, which translocates to the liver cell membrane. The LDL and VLDL particles in plasma bind to the LDL receptors and endocytose in hepatocytes, where their cholesterol component gets processed into bile salts, which are then excreted or recycled

This process increases the catabolism of LDL and VLDL cholesterol and results in further reduction of plasma cholesterol levels.

Statins reduce the level of total cholesterol, LDL-C, VLDL-C, triglycerides, apo-B, and increase the level of HDL-C

Apart from lowering lipid concentrations, statins also have cardiovascular protective effects (pleiotropic effects), which are primarily because of the inhibition of production of prenylated proteins (mainly farnesyl pyrophosphate and geranylgeranyl pyrophosphate) in the cholesterol biosynthetic pathway

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