Lipoprotein particles include chylomicrons, VLDL, LDL, and HDL. They transport lipids in plasma to and from tissues. Each particle has:

• A lipid core of triglycerides (TGs) and cholesterol esters
• A surface layer of apolipoproteins, phospholipids, and free cholesterol

Chylomicrons are the largest and least dense particles, while HDL is the smallest and most dense. Apolipoproteins have five major classes: A through E.

Chylomicrons:

1. They carry dietary TGs, cholesterol, fat-soluble vitamins, and cholesterol. They uniquely contain Apo B-48, which is formed after partial translation from the gene for Apo B-100.
2. The chylomicron synthesized in the intestinal mucosal cell is called a nascent chylomicron. When it reaches plasma, it receives:
   • Apo E (recognized by liver receptors for endocytosis)
   • Apo C (Apo C II activates lipoprotein lipase)
3. Lipoprotein lipase is present in capillary walls (except in the liver, which has hepatic lipase). Synthesis and transfer of this enzyme are stimulated by insulin. Heart muscle has high concentrations of this enzyme so it can easily use free fatty acids (FFAs) for energy. Lipoprotein lipase is activated by Apo C II and degrades TGs in chylomicrons. Chylomicron remnants are then taken up by the liver.
4. Patients with a deficiency of lipoprotein lipase or Apo C II (Familial Lipoprotein Lipase Deficiency or Type I Hyperlipoproteinemia) have very high chylomicrons and TGs (1000 mg/dl or more).

VLDLs:

1. They are produced in the liver and carry TGs from the liver to peripheral tissues.

2. Fatty liver occurs when there is an imbalance between hepatic TG synthesis and the secretion of VLDL.

3. 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.

4. CETP (cholesteryl ester transfer protein) helps exchange TGs and cholesterol esters between VLDL and HDL. After that, VLDL becomes LDL. IDL is a VLDL remnant.

5. In Type III Hyperlipoproteinemia (Familial Dysbetalipoproteinemia), patients are homozygous for Apo E2, a variation of Apo E that binds poorly to receptors, causing high cholesterol and premature atherosclerosis.

6. Apo E4 is associated with a high risk of Alzheimer’s disease.

   LDL:

7. LDL has a high concentration of cholesterol and cholesterol esters. Its main function is to provide cholesterol to tissues.

8. LDL binds to cell-surface LDL receptors that recognize Apo B-100, followed by clathrin-coated pit-mediated endocytosis.

9. In Type II Hyperlipidemia (Familial Hypercholesterolemia), there is a deficiency of LDL receptors, causing high LDL, high cholesterol, and premature atherosclerosis. Increased activity of a protease that degrades the receptor, or a defect in Apo B-100 that reduces binding to the receptor, can also cause the disease.

10. SRE and SREBP2 (steroid regulatory element binding protein) are involved in regulating the LDL receptor gene.

11. If cholesterol is not required by the cell, it is esterified by ACAT (acyl CoA cholesterol transferase), converting it to cholesterol ester that is stored in the cell.

12. Oxidized LDL is a precursor for plaques. It is engulfed by macrophages expressing scavenger receptors, which then turn into foam cells.

HDL:

1. Apo A1 is the main apolipoprotein in HDL.
2. HDL serves as a circulating reservoir for Apo C II and Apo E. Nascent HDL is disc-shaped; it takes up cholesterol from peripheral tissues and returns it to the liver.
3. Cholesterol is esterified in HDL by LCAT (lecithin cholesterol acyl transferase). HDL then becomes spherical. This process is called reverse cholesterol transport (from tissues to liver).
4. HDL binds to the liver at the SR B1 receptor (scavenger receptor class B type 1).

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: Lipoprotein(a) is associated with increased risk of heart disease. Levels are determined by genetics. Trans fats can increase levels, while niacin reduces levels. It has apolipoprotein (a), similar to LDL. Apo (a) is structurally similar to plasminogen (a clot-lysing agent). Elevated Lp(a) 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 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 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 I hypercholesterolemia, patients do not develop CAD although their triglycerides are elevated.

Types of hyperlipoproteinemias

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