Flashcards in Cholesterol Deck (73)
Triacylglycerol / 5
Where is cholesterol synthesized?
In the cytosol of all cells but mostly in liver, intestine, adrenal cortex, and reductive tissues
Function of cholesterol
- structural component of membranes
- precursor of bile salts, steroids, vitamin D
What are the main structural components of cholesterol?
- 4 fused rings
- hydrocarbon tail
- OH group on C-3
- Double bond at C5-C6
Where does de novo synthesis of cholesterol occur?
Liver and intestine
What is the source of carbon atoms for cholesterol?
What is the major cofactor in the synthesis of cholesterol? How many are used up?
Which enzyme is responsible for the rate limiting step in the synthesis of cholesterol? What is the product of this step?
The step is catalyzed by HMG-CoA reductase. The product is Mevalonic acid
What are the two enzymes responsible for the esterification of cholesterol?
ACAT - There's A CAT in the liver
LCAT - For HDL, in order for it to be packaged into HDL from the peripheral tissues.
In order to maintain homeostasis, what does the body do when there is excess cholesterol?
- In other words, what are the feedback mechanisms
- too much cholesterol Activates ACAT to make more cholesterol esters, which inhibits The uptake into cells.
- reduces the level of HMG-CoA reductase through proteolysis (SREBP)
What two hormones regulate cholesterol synthesis? How do they do this? Is this short term or long term?
- Insulin causes an increase in HMG-CoA activity by dephosphorylating HMG. CoA Reductase
- glucagon causes a decrease in HMG-CoA activity by using AMPK to phosphorylates HMG CoA Reductase
It senses the concentration of cholesterol in the ER membrane. When the concentration of cholesterol gets too low, vesicles containing SREB2 pinch off of the ER membrane and head to the Golgi apparatus. SREBP2 is then cleaved and the N-terminal segment moves into the nucleus and enhances transcription of many genes including HMG-CoA reductase and LDL-receptors.
Statins are used to reduce the risk of heart disease. It does this by targeting HMG CoA reductase. Statins are analogs of HMG-CoA, the precursor that HMG-CoA Reductase acts on. Therefore, they fight to bind with HMG CoA Reductase and less cholesterol is made.
What is statins affects on LDL?
Because there is less cholesterol synthesis in the liver, the liver retrieves cholesterol from lipoproteins that are circulating around the body. Therefore, there is less circulating cholesterol in the body but the homeostasis is restored in the liver. This is accomplished by up regulating the quantity of LDL receptor molecules on hepatocytes in the liver.
Consequence of hypercholesteremia. It is a cutaneous deposition of lipidosis.
Smith-Lemli-Opitz Syndrome (SLOS)
Mutation in DHCR7, which is involved in the production of cholesterol. Therefore, not enough cholesterol is made.
The consequences of this are:
- microcephaly, ptosis, broad nasal bridge, upturned nose, micrognathia (small jaw), cleft palate.
- short thumbs, polydactyly, syndactyly of the second and third toes.
Mnemonic - SLOS IS NOT enough cholesterol
Surface - amphipathic lipids with phospholipids and unesterified cholesterol. Also have proteins on the surface.
Anhydrous core - Triacylglycerides and cholesterol found in the anhydrous core
They bind lipid in the blood in order to form lipoproteins. The term "apo" means that it is in it's lipid-free form.
- They act as recognition sites or ligands for receptors
- act as structural components
- act as activators or coenzymes for enzymes involved in lipid metabolism
Which lipoprotein has the Highest proportion of Protein?
HDL because if you just remember that it is the highest density then you will remember that it has the highest proportion of proteins.
What are the two Basic phases Of lipoprotein metabolism?
1) Processing - in which lipoproteins undergo changes in composition of both core and surface components while in transit in the blood, thus converting them into their remnant form.
2) Clearance - cleared from the blood via a receptor-mediated endocytic process in the liver as well as other tissues.
Where are each of. The 4 types of lipoproteins made?
Chylomicrons --- intestine
VLDL - liver
LDL - in circulation by the breakdown of IDL
HDL --- liver
How does Dietary cholesterol get into chylomicrons and into the liver?
Firstly, dietary cholesterol is only found in foods derived from animals. Once in the intestine, dietary cholesterol esters are hydrolyzed, along with other sterols and they enter a micelle with bile salts, fatty acids, and monoglycerides. Epithelial cells from the jejunum then take up sterols via binding to NPC1L1 followed by endocytosis. Then the epithelial cells release all of their sterols other than cholesterol. Then the cholesterol and other cholestoryl esters are incorporated into chylomicrons and they enter the liver.
What are the 3 lipoproteins found on HDL? WHat do they do?
Apo C-II - Lipoprotein lipase activator
Apo C-III - Lipoprotein lipase inhibitor
Apo E - ligand for a receptor mediated clearance of remnants of lipoproteins such as chylomicron remnants or VLDL by the liver.
What are the two triglyceride degrading enzymes?
It is an extracellular protein found on the walls of blood capillaries anchored to the endothelium. It interacts with the chylomicrons or VLDL to hydrolyze Triacylglycerol to free fatty acids plus glycerol. About 80% of the FFAs are transported to the tissues (heart, adipose, muscle) and 20% goes to the liver. If the FFAs are not used immediately then they are picked up by albumin and circulate through the body.
- Requires ApoC-II as a cofactor
1)It has phospholipase activity but for our concerns currently, it also has triglyceride hydrolase activity. It completes the final processing of chylomicron remnants
2)It hydrolyzes triglycerides in the final processing of IDL-->LDL in order to make FFAs from triglycerides. It is synthesized by hepatocytes and is present primarily on liver endothelial cells.
3)It also participates in the conversion of HDL2 to HDL3.
- does not need apoCII
How dietary cholesterol metabolized using chylomicrons?
As we said earlier, dietary cholesterol is taken up by epithelial cells of the jejunum via binding of NPC1L1 followed by endocytosis. Intestinal cells use "Microsomal triglyceride transfer protein (MTP)" to assemble chylomicrons from Apolipoprotein B-48, triglycerides, phospholipids, cholesterol, and cholestoryl esters. The chylomicrons are then exported into the lymphatic system and from there reach the subclavian vein via the thoracic duct. Once in the blood, chylomicrons gain ApoC-II and Apo E mostly from HDL. Through removal of triglycerides by lipoprotein lipase, chylomicrons become chylomicron remnants, thus making them small enough to fit into the Space of Disse in the liver. Then Hepatic Lipase removes more triglycerides. ApoE then binds to "LDL receptor mediated protein 1 (LRP1)" on hepatocytes and the remnants enter via endocytosis. Lysosomes then degrade the chylomicron remnants.
How long is the half life of a chylomicron?
In the order of. Minutes
How long is the half life of a VLDL?
On the order of hours