4. (C)Cholesterol and Lipoproteins Flashcards
Drugs that decrease Cholesterol Levels in Blood and their Mechanism of action
Lovastatin and other “statin” group of drugs are competitive inhibitors of HMG CoA reductase. So, they are used in clinical practice to reduce cholesterol level in blood.
Lipoprotein A
Lipoprotein (a)
i. Lipoprotein(a)orLp(a)should not be confused with apo-A (see Box 12.3). Lp(a) is very strongly associated with myocardial infarction and is sometimes called the “little rascal”.
ii. Lp(a),whenpresent,is attached to apo B-100 by a disulfide bond.
iii. In40%population,thereisnodetectablelevel of Lp(a) in serum. In 20% of population, the Lp(a) concentration in blood is more than 30 mg/dl; and these persons are susceptible for heart attack at a younger age.
iv. Lp(a) is associated with heart attacks at the age of 30 or 40 years. Indians have a higher level of Lp(a) than Western populations.
v. Lp(a)hassignificanthomologywithplasmino- gen. So it interferes with plasminogen activation and impairs fibrinolysis (Fig. 12.15). This leads to unopposed intravascular throm- bosis and possible myocardial infarction.
Apo-A is a constituent of HDL. This “A” is always written in capital letters. It is seen in all persons. It is anti-atherogenic.
Lp(a) is seen in high levels only in some persons. When present, it is associated with LDL. This “a” is always written in small letters. It is highly athero- genic and correlated with heart attaks in younger age group.
Reverse transport of cholesterol by HDL
Metabolism of HDL
The intestinal cells synthesise components of HDL and release into blood. The nascent HDL in plasma is discoid in shape (Fig. 12.16).
The free cholesterol derived from peripheral tissue cells are taken up by the HDL. The apo-A-l of HDL activates LCAT (lecithin cholesterol acyl transferase) present in the plasma. The LCAT then binds to the HDL disk. The reaction is shown in Fig. 12.17. The cholesterol from the cell is transferred to HDL by a cholesterol efflux regulator protein which is an ABC protein.
Lecithin is a component of phospholipid bilayer of the HDL disk. Structure of lecithin is shown in Chapter 7. The second carbon of lecithin contains one molecule of polyunsaturated fatty acid (PUFA). It is transferred to the third hydroxyl group of cholesterol to form choles- terol ester. The esterified cholesterol which is more hydrophobic, moves into the interior of the HDL disk.
This reaction continues; till HDL becomes spherical with a lot of cholesterol esters are formed. This HDL particle designated as HDL-3. Mature HDL spheres are taken up by liver cells by apo-A-l mediated receptor mechanism. HDL is taken up by hepatic scavenger receptor B1. Hepatic lipase hydrolyses HDL phospholipid and TAG, and cholesterol esters are released into liver cells. The cholesterol that reaches the liver is used for synthesis of bile acids or excreted as such in bile.
The scavenger receptor B1 (SR-B1) is identified as an HDL receptor with dual role in HDL metabolism. In liver and steroidogenic tissues, it delivers cholesteryl ester to tissues whereas in the tissues it is involved in reverse cholesterol transfer.
When the HDL-3 remains in circulation, the cholesterol ester from HDL is transferred to VLDL, IDL and LDL by a Cholesterol Ester Transfer Protein (CETP). This will help to relieve product inhibition of LCAT so that more cholesterol can be taken up. Triacyl glycerol from VLDL, IDL and LDL is transferred to HDL in exchange for the cholesterol ester. The HDL particles that are rich in triacyl glycerol and spherical are called HDL-2. These particles are first acted upon by hepatic triglyceride lipase (HTGL) before being taken up by scavenger B1 receptors in liver.
The efflux of cholesterol from peripheral cells to HDL is mediated by the ABC transporter protein. The reverse cholesterol transport to liver through HDL needs the activity of LCAT, CETP and Apo-D.
Key enzyme of cholesterol synthesis
HmG - coA reductase
Long-term regulation involves regulation of transcription of the gene for HMG CoA reductase. When sufficient cholesterol is present in the cell, transcription of the gene for HMG CoA reductase is suppressed, and cellular synthesis of cholesterol is decreased. When cholesterol in diet is low, synthesis is increased.
The enzyme is activated by
Insulin
Thyroxine
Inhibited by
Statins
Glucagon
Cortisone
Fig 12.6 A pg 149 important
Why HDL is good cholesterol
The level of HDL in serum is inversely related to the incidence of myocardial infarction. As it is “anti- atherogenic” or “protective” in nature, HDL is known as “good cholesterol” in common parlance. It is convenient to remember that “H” in HDL stands for “Healthy”.
HDL level below 35 mg/dl increases the risk,
while level above 60 mg/dl protects the person from coronary artery diseases.
Importance of LCAT and CETP
LCAT is required for esterification of cholesterol.
CETP is required for transfer of cholesterol Ester from HDL to LDL and VLDL.
