Cholesterol transport and Tangier disease

Tangier disease is a disease of cholesterol transport. The first case was identified in a patient who lived on the island of Tangier and who had characteristic orange-colored tonsils, a very low HDL level, and an enlarged liver and spleen. Due to a mutation in the transport protein the cholesterol cannot properly exit the cell to bind to apo A (that forms HDL). This results in a very low HDL levels.

Cholesterol obtained by HDL from cell membranes is converted to cholesterol esters.

Which of the following enzymes catalyzes the esterification of cholesterol?

A. HMG Co A reductase

B. Lecithin: cholesterol acyl transferase

C. 7-Alpha hydroxylase

D. Acyl: Cholesterol acyl transferase

E. Thiophorase

The correct answer is- B- Lecithin: cholesterol acyl transferase. The cholesterol efflux is brought about by esterification of cholesterol under the effect of LCAT.

LCAT (Lecithin Cholesterol Acyl Transferase) enzyme catalyzes the esterification of cholesterol to form Cholesteryl ester. The reaction can be represented as follows-

Reaction by LCAT

Basic concept

HDL scavenges extra cholesterol from peripheral tissues by reverse cholesterol transport.

A receptor called, scavenger receptor B1 (SR-B1) has been identified as an HDL receptor with a dual role in HDL metabolism.

1) Extraction of cholesterol- In the peripheral cells, SR-B1 mediates the acceptance of cholesterol from the cells by HDL (Figure-1).

HDL is synthesized and secreted from both liver and intestine. Nascent HDL consists of discoid phospholipid bilayer containing apo A and free cholesterol. LCAT and the LCAT activator apo A-1,bind to the discoidal particles, and the surface phospholipid and free cholesterol are converted into cholesteryl esters and lysolecithin (figure-2).The nonpolar cholesteryl esters move into the hydrophobic interior of the bilayer, whereas lysolecithin is transferred to plasma albumin. Thus, a nonpolar core is generated, forming a spherical HDL covered by a surface film of polar lipids and apolipoproteins. This aids the removal of excess unesterified cholesterol from lipoproteins and tissues (Figure-1).

2) Delivery of cholesteryl esters-In the liver and in steroidogenic tissues, SR-B1 binds HDL via apo A-I, and cholesteryl ester is selectively delivered to the cells.


Reverse cholesterol transport

Figure-1-Reverse cholesterol Transport. Free cholesterol collected by the nascent HDL is converted to cholesteryl ester by LCAT. Cholesteryl esters are transported to liver cells through SR-B1 receptors or they are transferred to VLDL and chylomicrons through CETP (Cholesteryl ester transfer protein, and then transported to liver through LDL receptors (apo-B100/E).

ATP-binding cassette transporter A1 (ABCA1)

A second important mechanism for reverse cholesterol transport involves the ATP-binding cassette transporter A1 (ABCA1). ABCA1 is a member of a family of transporter proteins that couple the hydrolysis of ATP to the binding of a substrate, enabling it to be transported across the membrane. ABCA1 preferentially transfer cholesterol from cells to poorly lipidated particles such as pre -β-HDL or apo A-1, which are then converted to mature HDL (HDL3) via discoidal HDL

Pre – β HDL is the most potent form of HDL inducing cholesterol efflux from the tissues.

HDL cycle

Figure-2-HDL is synthesized both from liver and small intestine; the nascent HDL has a discoidal shape. HDL3, generated from discoidal HDL by the action of LCAT, accepts cholesterol from the tissues via the SR-B1 and the cholesterol is then esterified by LCAT, increasing the size of the particles to form the less dense HDL2.  HDL3 is then reformed, after selective delivery of cholesteryl ester to the liver via the SR-B1. This interchange of HDL2 and HDL3 is called the HDL cycle. Free apo A-I is released by this process forms pre β HDL after associating with a minimum amount of phospholipid and cholesterol. ABC-1 receptor is for providing cholesterol to poorly lipidated pre-β HDL.

Tangier disease is one of the most severe forms of familial high-density lipoprotein (HDL) deficiency. It is characterized by severe plasma deficiency or absence of HDL, apolipoprotein A-I (apoA-I, the major HDL apolipoprotein) and by accumulation of cholesteryl esters in many tissues throughout the body. The biochemical signs of this condition are plasma HDL concentrations less than 5 mg/dL, low total plasma cholesterol (below 150 mg/dL), and normal or high plasma triglycerides. Tangier disease is caused by mutations in the ‘ATP-Binding Cassette transporter A1’ (ABCA1) gene, which encodes the membrane transporter ABCA1. This transporter plays a key role in the first step of reverse cholesterol transport, through which the efflux of free cholesterol from peripheral cells is transferred to lipid-poor apo A-I.

The Tangier disease clinical phenotype is inherited as an autosomal recessive trait.

The patients present with large, yellow-orange tonsils, symptoms of neuropathies hepatomegaly, splenomegaly, premature myocardial infarction  or stroke, thrombocytopenia, anemia, gastrointestinal disorders and corneal opacities. To date there is no specific treatment for Tangier disease. Old and recently designed drugs, known to increase HDL levels, have been shown to be ineffective in Tangier patients.

As regards other options

A. HMG Co A reductase- is the key regulatory enzyme of pathway of denovo synthesis of cholesterol. This enzyme is competitively inhibited by Statins.

C. 7-Alpha hydroxylase- Is the regulatory enzyme of pathway of bile acid synthesis from cholesterol.

D. Acyl: Cholesterol acyl transferase is another enzyme for esterification of cholesterol. It is an intracellular enzyme, and the synthesized cholesteryl esters are stored in the cells.

E. Thiophorase is an enzyme for utilization of ketone bodies, it catalyzes the transfer of Co A tail to acetoacetate (ketone body) from succinyl co A  forming  Acetoacetyl Co A and succinate. Acetoacetyl co A is further metabolized forming2 molecules of Acetyl co A that are completely oxidized in the TCA cycle.


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