Lipoprotein particles are Chylomicrons, VLDL, LDL and HDL. They transport lipids in the plasma to and from tissues. They are composed of a lipid core of TGs and Cholesterol esters surrounded by apolipoproteins, phospholipids and free cholesterol. Chylomicrons are the largest in size but lowest in density while HDL is the densest and smallest. Apolipoproteins have 5 major classes – A to E.
Chylomicrons:
VLDLs:
They are produced in the liver and they carry TGs from liver to peripheral tissue.
Fatty liver occurs when there is an imbalance between hepatic TG synthesis and the secretion of VLDL.
Abetalipoproteinemia is a hypolipoproteinemia caused by a defect in microsomal TG Transfer Protein (MTP), leading to an inability to load Apo B with lipids. No VLDL or chylomicrons are formed, and TGs accumulate in the liver and intestine.
CETP (Cholesteryl ester transfer protein) helps in the exchange of TGs and Cholesterol esters between VLDL and HDL. After that VLDL becomes LDL. IDL is a VLDL remnant.
In Type III Hyperlipoproteinemia or Familial Dysbetalipoproteinemia patients are homozygous for ApO E2, a variation of ApOE which binds poorly to receptors, causing high cholesterol and premature atherosclerosis.
ApOE4 is associated with a high risk of Alzheimer’s Disease.
LDL:
Has a high concentration of cholesterol and chol esters. The main function of LDL is to provide cholesterol to the tissues.
They bind to cell surface LDL receptors that recognize ApO B 100 followed by clathrin coated pits mediated endocytosis.
In Type II Hyperlipidemia or Familial Hypercholesterolemia there is a deficiency of LDL receptors causing high LDL, high cholesterol and premature atherosclerosis. Sometimes increased activity of a protease that degrades the receptor or defect in ApO B 100 that reduces its binding to the receptor can also cause the disease.
SRE and SREBP2 ( steroid regulatory element binding protein) are involved in the regulation of the LDL receptor gene.
If cholesterol is not required by the cell, then it is esterified by ACAT (acyl CoA cholesterol transferase) converting it to cholesterol ester which is stored in the cell.
Oxidized LDL is the precursor for plaques. It is engulfed by macrophages expressing scavenger receptors, which then turn into foam cells.
HDL:
Tangier disease: A transport protein called ABCA 1 is required for the efflux of cholesterol from tissues. Deficiency of ABCA 1 causes Tangier disease characterized by the absence of HDL.
Lipoprotein a: It is associated with increased risk of Heart Disease. Levels are determined by genetics. Trans fats can increase levels while niacin reduces levels. Has apolipoprotein (a), similar to LDL. Apo (a) is structurally similar to plasminogen (clot lysing agent). Elevated Lpa competes with plasminogen for binding to fibrin, decreasing the ability of plasmin to lyse fibrin clots. This causes increased blood clots and premature AMI.
Disorders of lipoprotein metabolism:
Hypertriglyceridemia is a condition in which triglyceride levels are elevated. It is often caused or exacerbated by uncontrolled diabetes mellitus, obesity, and sedentary habits. Hypertriglyceridemia is a risk factor for coronary artery disease (CAD) and acute pancreatitis.
Hyperlipoproteinemia is a metabolic disorder characterized by abnormally elevated concentrations of specific lipoprotein particles in the plasma. It causes triglyceride elevations in most cases.
Hyperlipidemia (elevated plasma cholesterol or triglyceride levels or both) is present in all hyperlipoproteinemias.
Diabetes mellitus, pancreatitis, renal disease, and hypothyroidism are the common causes of secondary hyperlipidemias.
What is the source of increased cholesterol ? - HDL, LDL and/or IDL
What is the source of increased triglycerides ? - VLDL and /or Chylomicrons
In Type 1 hypercholesterolemia patients do not develop CAD although their triglycerides are elevated.
Type | Defect | Clinical features | Laboratory findings |
Type I Hypercholesterolemia or Familial Lipoprotein Lipase Deficiency | Deficiency of Lipoprotein Lipase or ApO C II ; AR | Pancreatitis, hepatosplenomegaly, eruptive xanthomas, lipemia retinalis | Very high Chylomicrons and TGs -1000 mg/dl or more; elevated cholesterol |
IIa or Familial Hypercholesterolemia | May be polygenic or AD inheritance; Dysfunction or absent LDL receptor | Premature CAD and atherosclerosis; Tendon xanthomas | Cholesterol and LDL |
IIb or Familial combined hyperlipidemia | AD; Multiple defects of various apolipoprotein and LPL genes | Xanthomas, increased risk of CAD and atherosclerosis | Cholesterol, LDL, VLDL and triglycerides |
III or Dysbetalipoproteinemia | Defective ApO E; most cases AR , some AD | Palmar xanthoma; tuberoeruptive xanthomas of elbows and knee, premature CAD and atherosclerosis | Cholesterol, Triglycerides and IDL |
IV or Familial Hypertriglyceridemia | AD | ? Early CAD | Triglycerides and VLDL |
V or hyper-pre beta-lipoproteinemia | Very rare; unknown defect | Eruptive xanthomas, pancreatitis, increased risk of CAD and atherosclerosis | Cholesterol, triglycerides, VLDL and chylomicrons |
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