Explain the function and regulation of HSL.
- HSL=hormone sensitive lipase - In adipose tissue, HSL releases FFAs into blood by cleaving TAGs into glycerol and FAs - Inhibited by insulin
How do FFAs travel in blood? Why is this transport method important?
- They bind to hydrophobic pockets in albumin. - Don’t need to synthesize FFA transporters when we are in a starved state and need FFAs as albumin is always present.
Why is transportation of lipids problematic?
- FAs are mostly hydrophobic - TAGs are completely hydrophobic - Cholesterol is hydrophobic mostly
How are TAGs and cholesterol transported?
- They are transported inside of carriers known as lipoproteins – VLDL, IDL, LDL and HDL
What are chylomicrons? Where are they made? Are they made in liver?
- Made by enterocytes in intestine, these transport dietary lipids from site of absorption to adipose tissue. - Not made in liver
What are lipoproteins? What are the types? What are they composed of besides what they carry?
- Are carriers of triacylglycerol and cholesterol - VLDL, IDL, LDL and HDL - Composed of phospholipid/cholesterol coat that has apoproteins embedded in it
Types of apoproteins and functions?
- Apoprotein A: activates LCAT (lecithin:cholesterol acyltransferase), which generates cholesterol esters from cholesterols. Extracts lipids from membranes for reverse transport. - Apoprotein B: structural protein, interacts with lipoprotein receptors and mediates uptake of particle into target cells - Apoprotein C: modulate lipoprotein lipase (LPL) activity, which liberates FFAs and glycerol from lipoproteins - Apoprotein E: bind to receptors to allow removal of remnant particles from circulation
What is the function of apoprotein A?
- activates LCAT (lecithin:cholesterol acyltransferase), which generates cholesterol esters from cholesterols. Extracts lipids from membranes for reverse transport.
What is the function of apoprotein B?
- structural protein, interacts with lipoprotein receptors and mediates uptake of particle into target cells
What is the function of apoprotein C?
- modulate lipoprotein lipase (LPL) activity, which liberates FFAs and glycerol from lipoproteins
What is the function of apoprotein E?
- bind to receptors to allow removal of remnant particles from circulation
Describe role of chylomicron, where synthesized, association with apoproteins, source of apoproteins, destination of contents and formation / fate of chylomicron remnant.
What apoproteins do chylomicrons associate with? Where?
- Chylomicrons in enterocytes associate with ApoB-48 - After entering into serum, CM now associates with ApoC and ApoE, which is receives from HDL
Describe role of VLDL, IDL and LDL. Include where each are synthesized/formed, association with apoproteins, source of apoproteins, destination of contents and fate of lipoprotein.
What apoproteins do VLDL associate with? IDL? LDL? Where?
- VLDL associates with ApoB100 in hepatocytes - VLDL in serum associates with apoE and apoC obtained from HDL - IDL remains associated with all 3 per above - LDL remains associated with all 3 per above
Describe role of HDL. Include where synthesized, association with apoproteins, source of apoproteins, destination of contents and fate of this lipoprotein.
What apoproteins do HDL associate with? Where?
- Nascent HDL associates with apoE,C and A in hepatocytes.
T2D patients present with high serum LDL even when serum glucose is well controlled. Where does this lipid abnormality originate? Why does it occur?
- Type 2 diabetics are insulin insensitive - As a result of insulin signaling stating to the body that glucose is in abundance and should be taken up, fatty acids are still being released from adipose tissue and the liver has to repackage large amounts of these, which in turn means that LDL levels are high.
Explain what the overflow pathway of lipid metabolism is.
- When the liver sends out more lipids in VLDL particles than the body can consume, the blood concentration of LDL increases. These LDLs instead of being returned and degraded by liver, bind to other receptors in the body such as macrophages (primarily) and peripheral cells.
Why is LDL considered atherogenic?
- Result of too much cholesterol / lipids or low concentration of LDL receptors or issue with receptor causes accumulation of LDL in the serum. - Many tissues have LDL receptors including macrophages. When macrophages take up LDL, they have no mechanism to degrade them especially when taken up in plentiful amounts. LDLs form patch in macrophages underneath epithelial membrane, secrete cytokines and start inflammatory process. This process results in oxidation / rancidity and causes plaques to rupture in blood vessels, which causes heart attacks/strokes.
Describe pathology of familial hypercholesterolemia. What is the presentation?
- Autosomal dominant disorder resulting from defects in LDL receptor. As a result, serum lipid concentrations are elevated and result in high levels of LDL in the blood serum. As a result of the overflow pathway into macrophages, atherosclerotic changes in blood vessels occur leading to higher incidences of CVD in the 3rd and 4th decades of life. - These individuals present with xanthomas (deposition of lipis) to joints and tendons. Lab studies indicate elevelated cholesterol and triglyceride levels.