Lipids and Lipoproteins Flashcards
TAGS are the major storage form of fatty acids with a glycerol backbone and 3 FA.
TAGS have ____ more energy than stored glycogen (carbs).
7x
What are our three sources of TAGS?
- Dietary TAGS, processed in our intestinal cells.
- De novo TAG from our hepatocytes and adipocytes
Describe the process of TAG synthesis in the intestines
1. Dietary TAGS are consumed
2. Pancreatic lipases in the intestinal lumen [TAG–> MAG and 2 FA].
3. MAG and 2 FA go absorbed into the intestinal cell
4. [MAG + 2 FA] –> [fatty acyl CoA synthetase]–> Fatty acyl CoA
5. Fatty acyl CoA–> DAG
6. DAG–> TAG
7. TAG + apolipoproteins + other lipids–> [CHYLOMICRONS]
8. Chylomicrons then enter the lymphatic system
9. Exit the thoracic duct
10. Go into the blood.
If we are starving, are we forming chylomicrons?
No, because we are not ingesting dietary TAGS.
What promotes TAG synthesis in the intestines?
Dietary TAGS
What are the two ways we can make TAGs in the liver?
1. Glycolysis
2. De novo synthesis
Describe the process of TAG synthesis in the liver
A. Glycolysis
- Glucose (main driver) undergoes glycolysis–> DHAP
- DHAP–> [GAP3DH]–> G3P
*Glycerol–>[Glycerol kinase]–> G3P
B. De novo synthesis
-Acetyl coA–> FA
FA–> [Fatty acyl CoA synthetase]–> Fatty acyl coA
C. Common pathway
- G3P + FFA
- DAG–> TAG
- TAG + apolipoproteins+ lipids+ cholesterol–> VLDL
- VLDL–> bloodstrem
If you want to inhibit the formation of of G3P from glycerol, and not impact any other cell in the body, what enzyme would you target?
Glycerol kinase- it is SPECIFIC to the liver.
What makes the backbone of our TAG?
Glycerol is made from G3P
What promotes the TAG synthesis in hepatocytes?
Excess carbohydrates
What are our sources of TAG in adipocytes (3)?
1. Chylomicrons
2. VLDL
3. Glucose
Describe the process of TAG synthesis in the adipocytes
A. Glycolysis
- Glucose enters the adipocyte via GLUT-4 transporters
- Glucose–> GAP3DH–> G3P
B. Chylomicrons and VLDL
- Chylomicrons and VLDL in the bloodstrem are broken down via capillary lipoproitein lipase into FA
- FA–> Fatty Acyl Co-A
C. Common Pathway
- Fatty acyl Co-A+ G3P
- DAG–TAG
–> stay in adipocytes; stored.
In adipocytes, what causes glucose to enter the cell and VLDL and chylomicrons to be broken down into FA, which will then enter the adipocyte?
+ insulin
TAG synthesis in the adipocytes is promoted by excess _______.
Carbs
and
fats
What is the only cell that stores TAGs?
Adipocytes
Where does mobilization of TAGS occur?
Adipocytes, because they are the only cell that stores the adipocytes.
Describe the process of mobilization of TAGs.
Occurs in the adipocytes
1. TAGS–>[ATGL* and hormone sensitive lipase]–>DAG, with release of a FA
2. DAG–>[hormone sensitive lipase* and lipoprotein lipase]–> MAG, with release of a FA
3. MAG–> [MAG lipase]–> free glycerol, with release of a FA
4. Short chain FA leave the adipocyte and undergo B oxidation in mT (long chain FA do the same, however they have to be bound to albumin).
Describe how we activate hormone sensitive lipase.
+ Glucagon
+NE
+ EPI
What enzymes are involved in the breakdown of TAG? (4)
- ATGL
- Hormone-sensitive lipase (activated by glucagon, EPI and NE)
- Lipoprotein lipase
- MAG lipase
What modulates the activity of HSL?
Hormones (glucagon, EPI) bind to a GCPR.
- Glucagon is relased when we are hungry
- EPI is released when we are excercising
GCPR will then increase AC, cAMP, PKA
PKA phosphorylates HSL to activate it.
Thus, phosphorylation.
What inhibits HSL phosphorylation?
Fed status (insulin)
because we do not want to break down the TAG
When we are in fed state, how do we inacitvate HSL?
Protein phosphatase 1 (PP1) dephosphorylates and inactivates HSL
What happens if we knockout hormone sensitive lipase?
Increase in DAG
What are perilipins?
Perilipins control lipolysis by coating lipids in adipocytes and muscle cells, proteing them from being targeted by HSL.
Too much perilipin causes what?
What about knocking it out?
Overexpression- Inhibits lipolysis
Knocking out- increase in lipolysis
Cholesterol is made by what cells and what is its fate?
What is the substrate for cholesterol?
The substrate for cholesterol is acetyl-coA.
Cholesterol is made by the liver, and then packaged into VLDL.
Lipoproteins transport cholesterol, cholesterol esters, TAGS and fat soluble vitamins.
Cholesterol is hydrophobic and not soluble in the blood. Thus, why is its concentration in the blood high?
Cholesterol concentration is high in the blood because it is packaged into VLDL.
What is the structure of lipoproteins?
Outside of the lipoprotein is made of one layer of phospholipids, free cholesterol and apoplipoproteins.
The inside, has TAGS and cholesterol esters.
Lipoproteins contribute to lipid metabolism.
How?
-Act as ligands that bind to receptors and internalize lipoproteins
-Also activate many enzymes
What are the 5 different types of lipoproteins?
1. Chylomicrons
2. VLDL
3. Intermediate density lipoproteins
4. LDL (bad cholesterol)
5. HDL (good cholesterol)
Which lipoprotein has the most TAGs and least proteins?
Which lipoproteins have the least TAGS and most proteins?
Chylomicrons–> most TAGs and least proteins
HDL–> most proteins and least TAGS
What apoproteins are on chylomicrons?
- ApoB-48–> helps transport in blood
- ApoC-II–> -activates the capillary lipoprotein lipase
- ApoE–> allows reuptake by the liver
What apoproteins are on VLDL?
1. ApoB-100–> allow uptake into cells
2. ApoC-II–> activate capillary lipoprotein lipase
3. ApoE–> Allows uptake by the liver
What apoproteins are on IDL?
Same as VLDL except ApoC-II- thus does not activate CLL
What apoproteins are on LDL?
Only ApoB-100- allow uptake into cells.
If LDL is taken up by a cell, its good. If it lingers in our blood, it can cause a build up of plaque.
What apoproteins are on HDL?
1, ApoC-11 (activates CLL)
2. ApoE (allows utake by the liver)
3. ApoA-I
How do we process chylomicrons (make and degrade)?
—-Maturation—
- Nascent chylomicrons (those with only Apo-B48) are made in the SI–> lymphatic system–> thoracic duct–> blood stream
- HDL adds ApoC-II and Apo-E to the nascent chymicron–> mature chylomicron
—-Breakdown—-
- Capillary lipoprotein lipase breaks down TAG–> glycerol and FFA and releases ApoC-II
- Chylomicron remant is made.
- ApoE binds to its receptor on the liver and it is endocytozed
Describe the process of VLDL, IDL and LDL processing.
- VLDL (ApoC-II, ApoE, ApoB-100) are made in the liver–> blood stream
- [VLDL]–>+capillary lipoprotein lipase is activated, causing the release of ApoC-II, glycerol and FFA–> [IDL]
- ApoE on IDL binds to the ApoE-R on the hepatic cells, delivering cholesterol
- Hepatic lipoprotein lipase acts on IDL and causes it to lose TAGS and ApoE –>[LDL]
- ApoB-100 on LDL binds to ApoB-100-R and deliver cholesterol to liver and peripheral tissue.
How do we uptake LDL?
LDL receptor gets recycled and goes to the surdface of the cell to attract more LDL.
What are the beneficial effects of HDL?
- High HDL–> decrease risk for coronary artery disease (CAD)
- important for maturation of chylomicrons
- Reverse cholesterol transport: removes LDL from periphery and takes it to the liver where it is recycled and processed.
- Anti-oxidant and anti-inflammatory effects
- Weight loss
What helps in the maturation of the chylomicron?
HDL- donates Apo-E and Apo-C-11
Type I hyperchylomicronemia
Cause:
Effects:
Cause: Deficiency in Apo-CII or lipoprotein lipase
Effects: Increase chylomicrons and TAGS
Type II hypercholesterolemia
Cause:
Effects:
Cause: LDL receptor is completely (IIa) or partially defective (IIb)
Effects: Increases cholesterol and LDL,
TAGs are normal in IIa but inncreased in IIb,
VLDL is increase in IIb
Type 1 hyperchylomicronemia is the same thing as type I hyperlipoproteinemia.
In this, we cannot do what?
What cause it?
We cannot hydrolyze TAGS in chylomicrons and VLDL due to a deficiency in lipoprotein lipase or Apo C-II.
Type 1 hyperchylomicronemia (type I hyperlipoproteinemia)
Primary LPO deficiency occurs when?
Apo C-defiency occurs when?
Plasma TAG levels are?
Clinical symptoms?
Tx?
Primary LPL deficiency occurs when? Infancy
Apo C-defiency occurs when? Adolescence
Plasma TAG levels are? >1000mg/dl
Clinical symptoms? Xanthomas
Tx? low fat diet
Type II hyperlipoproteinemia (hypercholesterolemia FH) is caused by?
What contrinutes to the 75% clearance of LDL in plasma?
- Defects in the LDL receptor uptaking LDL.
- Receptor-mediated endocytosis contributes to the 75% clearance of LDL in the plasma.
Type II hyperlipoproteinemia (hypercholesterolemia FH) causes
Artherolscerosis.
-Cant recognize ApoB-100 on the LDL
xanthomq
Type II hyperlipoproteinemia (hypercholesterolemia FH)
- Normal cholesterol
- Differences between heterozygous and homozygous
- Cholesterol is normally is 130-200 mg/dl
- Heterozygous is 300-500 mg/dl, while those that are homozygous have >800.
- Those heterozygous can use diets, statins, bile acid binding resins
- Homozygous needs LDL apheresis and liver transplantation.
Type II hyperlipoproteinemia (hypercholesterolemia FH) sx?
Xanthomas
CAD (arthersclerosis)
