Cholesterol Physiology

Cholesterol Physiology

By Dr Ananya Mandal, MD

Cholesterol is essential for all living organisms. It is synthesized from simpler substances within the body. Cholesterol can also be obtained from food. Saturated fats in food can be converted to cholesterol. This may lead to excessive cholesterol in blood.

High levels of cholesterol in blood circulation, depending on how it is transported within lipoproteins, are strongly associated with progression of atherosclerosis.

How much cholesterol does the body normally produce?

Normal adults typically synthesize about 1 g (1,000 mg) cholesterol per day and the total body content is about 35g.

Typical daily additional dietary intake, in the United States and similar cultures is about 200–300 mg. The body compensates for cholesterol intake by reducing the amount synthesized. This occurs by reduction of synthesis of cholesterol, reutilization of the existing cholesterol and excretion of excess cholesterol by the liver via the bile into the digestive tract.

Typically about 50% of the excreted cholesterol is reabsorbed by the small intestines back into the bloodstream for reuse.

Functions of cholesterol in the body

Cholesterol is essential for making the cell membrane and cell structures and is vital for synthesis of hormones, vitamin D and other substances.

• Cell membrane synthesis – Cholesterol helps to regulate membrane fluidity over the range of physiological temperatures. It has a hydroxyl group that interacts with the polar head groups of the membrane phospholipids and sphingolipids. These exist along with nonpolar fatty acid chain of the other lipids. Cholesterol also prevents the passage of protons (positive hydrogen ions) and sodium ions across the plasma membranes.
• Cell transporters and signalling molecules – The cholesterol molecules exist as transporters and signalling molecules along the membrane. Cholesterol also helps in nerve conduction. It forms the invaginated caveolae and clathrin-coated pits, including caveola-dependent and clathrin-dependent endocytosis. Endocytosis means engulfing of foreign molecules by the cell. Cholesterols help in cell signalling by assisting in the formation of lipid rafts in the plasma membrane.
• Cholesterol in the myelin sheaths – The nerve cells are covered with a protective layer or myelin sheath. The myelin sheath is rich in cholesterol. This is because it is derived from compacted layers of Schwann cell membrane. It helps in providing protection, insulation and allows more efficient conduction of nerve impulses.
• Role inside the cells – Within the cells, cholesterol is the precursor molecule in several biochemical pathways. For example, in the liver, cholesterol is converted to bile, which is then stored in the gallbladder. Bile is made up of bile salts. This helps in making the fats more soluble and helps in their absorption. Bile salts also aid in absorption of fat soluble vitamins like Vitamins A, D, E and K.
• Hormones and Vitamin D - Cholesterol is an important precursor molecule for the synthesis of Vitamin D and the steroid hormones like Corticosteroids, Sex-steroids (Sex hormones like Estrogen, Progesterone and Testosterone etc.)

Cholesterol synthesis

The liver is the primary organ that synthesizes cholesterol. About 20–25% of total daily cholesterol production occurs here. Cholesterol is also synthesized to smaller extents in the adrenal glands, intestines, reproductive organs etc.

The synthesis of cholesterol begins with a molecule of acetyl CoA and one molecule of acetoacetyl-CoA, which are dehydrated to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA). This molecule is then reduced to mevalonate by the enzyme HMG-CoA reductase. This step is an irreversible step in cholesterol synthesis. This step is blocked by cholesterol lowering drugs like Statins.

Mevalonte then converts to 3-isopentenyl pyrophosphate. This molecule is decarboxylated to isopentenyl pyrophosphate. Three molecules of isopentenyl pyrophosphate condense to form farnesyl pyrophosphate through the action of geranyl transferase. Two molecules of farnesyl pyrophosphate then condense to form squalene. This requires squalene synthase in the endoplasmic reticulum. Oxidosqualene cyclase then cyclizes squalene to form lanosterol. Lanoststerol then forms cholesterol.

Regulation of cholesterol synthesis

Biosynthesis of cholesterol is directly regulated by the cholesterol levels present. When too much intake of cholesterol from food is detected there is a reduction in endogenous cholesterol synthesis. The main regulatory mechanism is the sensing of intracellular cholesterol in the endoplasmic reticulum by the protein SREBP (sterol regulatory element-binding protein 1 and 2).

HMG CoA reductase contains a membrane and a cytoplasmic domain. The membrane domain can sense for its degradation. Increasing concentrations of cholesterol (and other sterols) cause a change in this domain and makes it more susceptible to destruction by the proteosome. The activities of this enzyme is also reduced by phosphorylation by an AMP-activated protein kinase.

Cholesterol from food

There are several animal fats that are sources of cholesterol. Animal fats are complex mixtures of triglycerides and contain lower amounts of cholesterols and phospholipids.

Major dietary sources of cholesterol include cheese, egg yolks, beef, pork, poultry, and shrimp. Cholesterol is absent in plant based foods, however, plant products such as flax seeds and peanuts may contain cholesterol-like compounds called phytosterols. These are beneficial and help in lowering the cholesterol levels.

Saturated fats and trans fats in food are the worst culprits that raise blood cholesterol. Saturated fats are present in full fat dairy products, animal fats, several types of oil and chocolate. Trans fats are present in hydrogenated oils. These do not occur in significant amounts in nature. These are found in many fast foods, snack foods, and fried or baked goods.

Transport of cholesterol and lipids

There are two primary pathways of lipid transport. These are:

Exogenous pathway (transport of dietary lipids)

This pathway permits efficient transport of dietary lipids. By this the dietary triglycerides are hydrolyzed by pancreatic lipases within the intestines and are emulsified with bile acids to form micelles. The chylomicrons thus formed are secreted into the intestinal lymph and delivered directly to the blood. These are then processed in the peripheral tissues before reaching the liver. The particles are acted upon bylipoprotein lipase (LPL). The triglycerides of chylomicrons are hydrolyzed by LPL, and free fatty acids are released. The chylomicron particle progressively shrinks in size and the cholesterol and phospholipids from it are transferred to HDL. The resultants are chylomicron remnants.

Endogenous pathway (transport of liver lipids)

This pathway deals with the metabolism of lipoproteins LDL (Low density lipoproteins), HDL (High density lipoproteins), VLDL (Very Low Density Lipoproteins) and IDL (Intermediate density lipoproteins).

VLDL particles are similar to chylomicrons in protein composition. But these contain apoB-100 rather than apoB-48 and have a higher ratio of cholesterol to triglyceride. The triglycerides of VLDL are hydrolyzed by LPL. These then become IDL.

The liver removes 40 to 60% of VLDL remnants and IDL by LDL receptor. The cholesterol in LDL accounts for 70% of the plasma cholesterol in most individuals. Lipoprotein(a) [Lp(a)] is a lipoprotein similar to LDL in lipid and protein composition. It has an additional protein called apolipoprotein(a) [apo(a)].

Reverse cholesterol transport

The predominant route of cholesterol elimination is by excretion into the bile. Cholesterolfrom cells is transported from the plasma membranes of peripheral cells to the liver HDL-mediated process termed  reverse cholesterol transport.