Lipid Foundations and Lipid Disorders

What is a lipoprotein

It is a lipid plus a protein

What are the five major classes of lipoproteins

Cholesteryl esters, phospholipids, triglycerides, cholesterol, free fatty acids

What is hyperlipidemia

Elevation in any lipoprotein species

What is elevation in triglycerides called

Hyperlipemia

Main purpose of HDL

To carry cholesterol from peripheral tissue to the liver

Main purpose of LDL

To carry cholesterol from the liver to the peripheral tissue

Function of Cholesterol

It is a component of cell membranes. It is the precursor to vitamin D, adrenal hormones like cortisol and aldosterone, and sex hormones. It is a precursor for bile acids. Important for brain function.

Composition of lipoprotein

Nonpolar core that consists of triglycerides and cholesterol esters. It is surrounded by an amphipathic polar monolayer of phospholipid, head of free cholesterol, and apolipoproteins

Purpose of lipoproteins

To transport hydrophobic insoluble lipids

Purpose of apolipoproteins

Serves as ligands in receptor mediated processes. Molecular navigators that direct lipoproteins to certain compartments and tissues.

How are triglycerides transported

Through VLDL and chylomicrons

Purpose of chylomicrons

Carry dietary lipids and deliver triglycerides to cells

Purpose of VLDL

Present in serum with HDL and LDL. Deliver triglycerides to cells.

Exogenous pathway

Refers to dietary lipid metabolism.

Endogenous pathway

Refers to lipid metabolism from within, focusing primarily on the liver and what is formed by the liver.

Reverse cholesterol transport

Refers to the process by which cholesterol is removed from tissue in the body and returned to the liver for disposal

Steps of the exogenous pathway

1. Dietary cholesterol and fatty acids are absorbed

2. Triglycerides are formed in the intestinal cell from free fatty acids and glycerol and cholesterol is esterified

3. Triglycerides and cholesterol combine to form chylomicrons

4. Chylomicrons enter the circulation and travel to peripheral sites

5. in peripheral tissues, free fatty acids are released from the chylomicrons by lipoprotein lipase to use as energy converted to triglyceride or stores in adipose

6. Remnants are used in the formation of HDL

Where are dietary lipids broken down upon consumption

The duodenum of the small intestine

How are lipids digested

Bile salts. They emulsify and solubilize lipids forming micelles. The micelles render the fats and make the cholesterol accessible to pancreatic lipase which then leads to the digestion of fat into free fatty acids and free cholesterol.

Steps of cholesterol entering the enterocyte

1. NPC1L1 transporter allows cholesterol into the cell

2. Some cholesterol is pumped back out into the lumen via ABCG5/G8

3. The triglycerides as free fatty acids enter via different transporters

Basic Steps of Chylomicron Formation

Assembly, Metabolism, Clearance

Steps of Chylomicron Assembly

Takes place in the smooth endoplasmic reticulum. ApoB is synthesized by ribosomes and MTP loads lipids (TGs and free fatty acids) onto ApoB “lipidating” it. The chylomicron is then excreted via exocytosis.

Where do Chylomicrons go after formation

They go into circulation where they encounter HDL which transfers Apo C and ApoE to the chylomicrons. It then encounters Lipoprotein lipase which removes the chylomicrons triglycerides forming chylomicron remnants. The remnants are then redirected to the liver where they will be taken up by LDL receptors and used to make VLDL.

Purpose of ApoB

Lipoprotein lipase recognizes ApoB

Basic steps of VLDL metabolim

Assembly, metabolism, clearance

How is VLDL assembled

The same as chylomicrons. ApoB lipidates triglycerides via MTP

Steps of the Endogenous pathway

1. VLDL is formed in the liver from triglycerides and cholesterol esters

2. They can be hydrolyzed by lipoprotein lipase to form IDL or VLDL remnants

3. VLDL remnants are cleared from the circulation or incorporated into LDL

4. LDL particles contain a core of cholesterol esters and a smaller amount of triglyceride

5. LDL is internalized by hepatic and non-hepatic tissues

6. In the liver LDL is converted into bile acids and secreted into the intestines

7. In non-hepatic tissues, LDL is Used in hormone production, cell membrane synthesis, or stored.

8. LDL is also taken up by macrophages and other cells which can lead to excess accumulation of the formation of foam cells which are important in plaque formation

Why are LDL receptors important

They are the main mechanism for clearing LDL from the bloodstream. Negative feedback decreased cholesterol synthesis.

How does LDL move cholesterol from the liver to extrahepatic cells

Cholesterol is synthesized in hepatocytes via HMG CoA reductase. It is then packaged with triglycerides and ApoB into VLDL. Then it is released into circulation. In circulation VLDL triglycerides are hydrolyzed by lipoprotein lipase to yield LDL. LDLs are also formed from the hydrolyzation of IDLs via hepatic lipase. The LDLs carry cholesterol from the liver to the extrahepatic tissues and are then taken back into the liver for cholesterol recycling. LDL receptors mediate the uptake of LDL CL both by extrahepatic tissues and by the liver, binding to ApoB.

Fate of IDL

Very similar to VLDL remnants. It can be taken up by the liver for further hydrolyzed into LDL via hepatic lipase

Steps of Reverse Cholesterol Transport (Tissue to Liver)

ApoA1 is synthesized in the liver which is then released as small pre-HDL particles. The HDL particles develop by taking up cholesterol from extrahepatic cells via ABC A1. LCAT further esterifies cholesterol so it can be used in HDL. HDL is further remodeled by CETP and LIPG. The HDLs containing excess cholesterol then re-enter hepatocytes via SRB1 receptors which recognize ApoA1. HDL can be released back into circulation to gather more cholesterol.

Why are HDLs beneficial to atherogenesis

They mediate cholesterol transport moving cholesterol away from macrophages and foam cells to the liver. They also have anti-inflammatory properties that inhibit plaque formation and expansion.

Why are ApoA1 levels important

Forms the backbone of HDL particles which are anti-atherogenic. Better reflect HDL function than HDL levels.

What enhances expression of ApoA1

PPAR - a

How does inflammation impair HDLs

Inflammation increases production of interleukin-6 which causes the liver to produce serum amyloid protein (SAA). This displaces ApoA1 from HDLs, altering them making them less effective. Oxidation.

Causes of atherogenesis

Inflammatory and oxidative remodeling of lipoproteins, abnormally high levels of LDL, abnormally low levels of HDL.

Steps from Coronary Atherogenesis to MI

1. Injury of epithelium

2. Inflammatory response/ oxidation of LDL

3. Macrophage migration and foam cell formation

4. Fatty streak formation

5. Partial occlusion of artery

6. Thrombus formation

7. Thrombus disruption

8. Occlusion of artery

9. Ischemia and MI

Oxidized LDL Particles

Oxidation shortens the fatty acids, forming whiskers. These are recognized by scavenger receptors on macrophages leading to the formation of foam cells.