Sunday, November 11, 2012

Reverse Cholesterol Transport and the Role of HDLc


Q.- What is Reverse cholesterol transport ? Explain the biological/clinical significance of this process.

Or
Discuss the concept of “reverse cholesterol transport” and indicate how its operation might contribute to a lowering of serum cholesterol.
or
Discuss the role of LCAT (Lecithin Cholesterol Acyl Transferase) in the cholesterol transport.
Answer-  The selective transfer of cholesterol from peripheral cells to HDLs, and from HDLs to the liver for bile acid synthesis, and to steroidogenic tissues for hormone synthesis, is a key component of cholesterol homeostasis. This is in part the basis for the inverse relationship seen between plasma HDL concentration and atherosclerosis, and because of this only HDL is designated as "Good cholesterol carrier".
HDL- HDL particles serve as  circulating reservoir of apo CII (apo protein that is transferred to VLDL and Chylomicrons, and is an activator of lipoprotein lipase), and apo E (the apoprotein required for the receptor-mediated endocytosis of IDls and chylomicron remnants (Figure-1)












Figure-1 Showing the structure of HDL. The outer shell is made by apoproteins, phospholipids and free cholesterol and the inner core is made by Cholesteryl esters and triglycerides.

HDL is synthesized and secreted from both liver and intestine (Figure -2). However, apo C and apo E are synthesized in the liver and transferred from liver HDL to intestinal HDL when the latter enters the plasma. Nascent HDL consists of discoid phospholipid  bilayer containing apo A and free cholesterol.















Figure-2- Showing the role of HDL in reverse cholesterol transport. HDL has four forms, Discoidal HDL, HDL3 , HDL2 and Pre β  HDL.( C- Cholesterol, CE- Cholesteryl Ester, LCAT- Lecithin choleterol Acyl Transferase, PL- Phospholipid.
Reverse cholesterol transport involves-
1) Efflux of cholesterol from peripheral cells and esterification to form cholesteryl ester by LCAT
LCAT ( Lecithin Cholesterol Acyl Transferase) enzyme catalyzes the esterification of cholesterol to form Cholesteryl ester.
The reaction can be represented as follows-
Lecithin + Cholesterol ---------->   Lysolecithin + Cholesteryl Ester
LCAT and the LCAT activator apo A-I—bind to the discoidal particles (Figure-1) and the surface phospholipid , free cholesterol  (extracted from peripheral cells) is converted into cholesteryl esters and lysolecithin .
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, pseudomicellar HDL covered by a surface film of polar lipids and apolipoproteins. This aids the removal of excess unesterified cholesterol from lipoproteins and tissues .
2) Binding of the cholesteyl ester-rich HDL(HDL2) to liver and steroidogenic cells, and the selective transfer of cholesteryl esters in to these cells)- Figure-2
HDL Receptor
The class B scavenger receptor B1 (SR-B1) has been identified as an HDL receptor with a dual role in HDL metabolism.
a) In the liver and in steroidogenic tissues, it binds HDL via apo A-I, and cholesteryl ester is selectively delivered to the cells, although the particle itself, including apo A-I, is not taken up.
b) In the tissues, on the other hand, SR-B1 mediates the acceptance of cholesterol from the cells by HDL, which then transports it to the liver for excretion via the bile (either as cholesterol or after conversion to bile acids) in the process known as reverse cholesterol transport (Figure 2).
HDL cycle
HDL3, generated from discoidal HDL by the action of LCAT (Figure-2) 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, either after selective delivery of cholesteryl ester to the liver via the SR-B1 or by hydrolysis of HDL2 Phospholipid and triacylglycerol by hepatic lipase (Figure-2).This interchange of HDL2 and HDL3 is called the HDL cycle (Figure -2).
Free apo A-I is released by these processes and forms pre-HDL after associating with a minimum amount of Phospholipid and cholesterol. Surplus apo A-I is destroyed in the kidney.
HDL Transporter
A second important mechanism for reverse cholesterol transport involves the ATP-binding cassette transporter A1 (ABCA1) (Figure-2). 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-HDL or apo A-1, which are then converted to HDL3 via discoidal HDL (Figure -2). Pre-β HDL is the most potent form of HDL inducing cholesterol efflux from the tissues.
Clinical Significance
LCAT deficiency- Complete absence (Familial LCAT deficiency) or partial (Fish eye disease) deficiency results in a marked decrease in HDL primarily as a result of the hyper catabolism of lipid poor HDLs.
Atherosclerosis- There is an inverse relationship between HDL (HDL2) concentrations and coronary heart disease. This is consistent with the function of HDL in reverse cholesterol transport. Atherosclerosis is characterized by the deposition of cholesterol and cholesteryl ester from the plasma lipoproteins into the artery wall. Diseases in which prolonged elevated levels of VLDL, IDL, chylomicron remnants, or LDL occur in the blood (eg, diabetes mellitus, lipid nephrosis, hypothyroidism, and other conditions of hyperlipidemia) are often accompanied by premature or more severe atherosclerosis.LDL:HDL cholesterol ratio a good predictive parameter.
Low HDL levels
Causes of low HDL levels
  • Severely reduced plasma levels of HDL-C (<20 mg/dL) accompanied by triglycerides <400 mg/dL usually indicate the presence of a genetic disorder, such as a mutation in apoA-I, LCAT deficiency, or Tangier disease.
  • HDL-C levels <20 mg/dL are common in the setting of severe hypertriglyceridemia,
  • HDL-C levels <20 mg/dL also occur in individuals using anabolic steroids.
  • Secondary causes of more moderate reductions in plasma HDL (20–40 mg/dL) should be considered like smoking, diabetes mellitus Type 2, Gaucher’s disease and malnutrition.
Management of low HDL levels
  •  Smoking should be discontinued,
  • Obese persons should be encouraged to lose weight,
  • Sedentary persons should be encouraged to exercise, and diabetes should be optimally controlled.
  •  When possible, medications associated with reduced plasma levels of HDL-C should be discontinued.
  • The presence of an isolated low plasma level of HDL-C in a patient with a borderline plasma level of LDL-C should prompt consideration of LDL lowering drug therapy in high-risk individuals.
  • Statins increase plasma levels of HDL-C only modestly (~5–10%). Fibrates also have only a modest effect on plasma HDL-C levels (increasing levels ~5–15%), except in patients with coexisting hypertriglyceridemia, where they can be more effective.
  • Niacin is the most effective available HDL-C–raising therapeutic agent and can be associated with increases in plasma HDL-C by up to ~30%, although some patients do not respond to niacin therapy.

 ------------------------------------------ Best Wishes: Dr.Ehab Aboueladab, Tel:01007834123 Email:ehab10f@gmail.com,ehababoueladab@yahoo.com ------------------------------------------
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