Lipoprotein Lecture (Lecture 1) Flashcards
Formula for total cholesterol
LDL cholesterol + HDL cholesterol + VLDL cholesterol
** VLDL cholesterol = triacylglycerol/5 **
How are lipid levels different than blood glucose levels?
Unlike tight regulation of blood glucose levels, lipids levels are variable among people. Things are more complicated, principally because they are many different lipoprotein species involved, each of which is able to undergo significant changes in composition and size and to interact with many target tissues.
Regulation of blood glucose levels
Blood glucose levels are tightly regulated and vary between 80 and 90 mg/dl after many hours of fasting
What is a cholesterol? Where is it synthesized?
Cholesterol is a lipid (very hydrophobic compound) synthesized by virtually all cells, but especially live, intestine, adrenal cortex and reproductive tissues
What are the functions of cholesterol?
(1) structural component of membranes
(2) precursor of bile salts, 5 major classes of steroid hormones, vitamin D
Is cholesterol required in the human diet?
Cholesterol is not required in the human diet because our cells can synthesize cholesterol de novo
Explain connection of cholesterol and cardiac pathologies
Cardiac pathologies associated with cholesterol stem from the regulation of its abundance in the serum, packages in lipoprotein particles, and the propensity of one class of these lipoproteins to accumulate in arterial walls.
What does the structure of cholesterol consist of?
(1) 4 fused rings
(2) a hydrocarbon “tail”
(3) -OH group on C-3
(4) double bond at C-5 to C-6
** These are reactive sites for esterification and oxidation-reduction reactions **
Characteristics of cholesterol
very hydrophobic compound, consists of four fused hydrocarbon rings, eight-carbon, branched hydrocarbon chain attached to carbon 17 of the D ring. Ring A has a hydroxyl group at carbon 3, and ring B has a double bond between carbon 5 and carbon 6
How is plasma cholesterol different from cholesterol in the membrane?
Most plasma cholesterol is in an esterified form (with a fatty acid attached at carbon 3, which makes the structure even more hydrophobic than free (unesterified) cholesterol. Cholesteryl esters are not found in membranes, and are normally present only in low levels in most cells.
What is the consequence of cholestrol’s hydrophobicity?
(1) must be transported in association with protein as a component of a lipoprotein particle
(2) solubilized by phospholipids and biles salts in the bile
Talk about the liver and cholesterol.
Think of the liver’s role with cholesterol as one like a pool. The liver is a pool filled with cholesterol, instead of water. You can put water into the pool or take water out of the pool.
Where does liver cholesterol come from?
(1) diet (via chylomicron remnants)
(2) local synthesis
(3) extrahepatic tissues (via HDL and LDL) - other cells synthesize cholesterol and ship it to the liver
What does the liver do with cholesterol?
can export the cholesterol:
(1) in VLDL
(2) excrete cholesterol in bile
(3) use cholesterol to convert it to bile salts (remember, cholesterol is a precursor to bile salts)
What are the different packaging types for cholesterol?
(1) Chylomicron - the lipoprotein particle derived from the intestine
(2) VLDL - lipoprotein from the liver
(3) LDL/HDL
* * to varying degrees each of the major lipoprotein particles function to transport cholesterol, to and from the peripheral tissues, to and from liver **
What is the only mechanism the body possesses to eliminate cholesterol?
Bile acids in the feces
Where does cholesterol synthesis take place in the cell?
Cytosol
What compound is the source for all carbon atoms in cholesterol?
Acetyl-CoA
What is the major co-factor required for cholesterol synthesis?
NADPH
What are the only two major organs that contribute to de novo cholesterol that we have to care about?
Liver and intestine
What is the enzyme that catalyzes the rate limiting step of cholesterol synthesis?
HMG CoA reductase
What does HMG CoA reductase?
(1) converts HMG CoA to mevalonic acid (mevalonate)
(2) 2 NADPH is used up
(3) releases free CoA
What does mevalonic acid give rise to?
Mevalonic acid gives rise to the isoprene squalene, which ‘folds up’
What does squalene give rise to?
After ‘folding up’ and after a series of intramolecular reactions give rise to lanosterol; lanosterol in turn is converted to cholesterol in many reactions
What does cholesterol synthesis require?
(1) requires several NADPH
(2) requires several ATP
Besides giving rise to cholesterol, what else does mevalonic acid give rise to?
Mevalonic acid gives rise not only to cholesterol, but also to terpenes (isoprenoids, sometims also called isoprenes), such as farnesyl pyrophosphate, dolichol, ubiquinones, and geranylgeranyl pyrophosphate
Purpose of farnesyl pyrophosphate and geranylgeranyl pyrophosphate?
Farnesyl pyrophosphate and geranylgeranyl pyrophosphate can be conjugaes with proteins and then serve as lipid anchors
Purpose of dolichol pyrophosphate?
Dolichol pyrophosphate is required for the dolichol pathway of N-linked posttranslational protein glycosylation.
Purpose of ubiquinones?
Ubiquinones can be reduced to ubiquinols, which can donate their electrons to the electrontransport chain as part of oxidative phosphorylation.
What is the consequence of esterification on cholesterol?
Esterifiation makes cholesterol more hydrophobic, enabling it to be pakages, and stored and transported easily
What enzymes are responsible for the esterification of cholesterol?
(1) ACAT
(2) LCAT
Where is LCAT found?
LCAT (lecithin cholesterol acyl transferase) is found in HDL
Where is ACAT found?
ACAT (acyl CoA choleserol acyl transerase in cells) is found epithelial cells of the intestine, hepatocytes, and steroid-producing cells (hepatocytes and steroid producing cells store cholesterol as cholesteryl esters inside lipid droplets in the cytosol, while most other cells contain virtually no cholesteryl esters)
What are the effects of excess cholesterol?
(1) activate ACAT to make cholesterol esters
(2) inhibit uptake of cholesterol into liver cells
(3) reduce levels of HMG-CoA reductase through
a. stimulates proteolysis of HMG CoA reductase
b. regulate its expression by influencing RNA polymerase II’s rate of HMG-CoA reductase
Effect of insulin on HMG-CoA reductase?
insulin stimulates HMG-CoA reductase; a signal of anabolism and growth; remember, insulin is released when glucose levels are elevated
(do not want to use acetly CoA to make cholesterol)
Effect of glucagon on HMG-CoA reductase?
glucagon inhibits HMG-CoA reductase ; a signal to preserve acetyl-CoA for the TCA cycle; remember, glucagon is release when glucose levels are low
How else is HMG-CoA Reductase modified?
covalent modification (phosphorylation or dephosphorylation)
When is HMG-CoA Reductase most active?
In its unmodified form
What is the result of phosphorylating HMG-CoA Reductase?
decreasing its activity
What enzyme phosphorylates HMG-CoA Reductase?
AMP-activated protein kinase, AMPK
Effect of glucagon and epinephrine on cholesterol biosynthesis?
Increase the activity of the phosphoprotein phosphatase inhibitor-1, PPI-1
(What does PPI-1 do? Inhibits phosphatase activity - inhibits the removal of phosphate groups)
Effect of insulin on cholesterol biosynthesis?
Insulin stimulates the removal of phosphates and, thereby, activates HMGR activity.
What is the role of HMGP phosphatase?
Remove phosphate from HMGR (stimulated by insulin)
What is the role of AMPK?
Add phosphate to HMGR (stimulated by glucagon, sterols, and high levels of AMP)
Who controls cholesterol synthesis transcriptionally?
SREBP2
What is SREBP2?
It is a cholesterol sensor that is the man regulator of HMG-CoA reductase activity. SREBP2 is an integral membrane protein of the endoplasmic reticulum that sense the concentration of cholesterol in the ER membrane. When the concentration of cholestrol in the ER is abnormally low, SREBP-2 containing vesicles form and move to the Golgi apparatus. There, proteases cleave SREBP2. The N-terminal segment of SREBP2 then moves into the nucleus and enhances transcription of several genes, including the genes for HMG-CoA reductase and LDL-receptors. When the concentration of cholesterol is high, there is no such stimulation of transcription by an SREBP2 fragment.
What is SREBP an abbreviation for?
Sterol regulatory element binding protein
What class of drugs target HMG-CoA reductase?
Statins (reduce the risk of heart disease)
How do statins reduce the risk of heart disease?
Statins are structural homologues of HMG-CoA, and compete for HMG-CoA binding on the reductase, reducing its ability to promote cholesterol synthesis
How do statins affect LDL concentrations?
Increases the rate of LDL removal from the circulation by stimulating the functional activity of hepatic LDL receptors or by stimulating the expression of LDL receptor molecules on hepatocytes
the lower the LDL …
the lower the risk for coronary artery disease (also called coronary heart disease)
high LDL …
associated with atherosclerosis
oxidized LDL leads to plaque
Problem with plaques
at some point, they rupture, and together with a newly forming blood clot, obstruct blood flow
What are xanthomas?
cutaneous depositions of lipidosis; contain cholesterol-laden foam cells. location depends on the cause of the dyslipidemia
Where do xanthelasmas form?
under the skin, typically of the eyelid
Patients with hypercholesterolemia (no hypertriglyceridemia) have what types of xanthomas?
tendon xanthomas, most often on the hands and feed
Patients with combined hypercholesterolemia and hypertriglyceridemia have what types of xanthomas?
tuberous xanthomas, which form over joint
What is SLOS?
A metabolic disorder caused by a mutation in the DHCR& gene on chromosome 11. This gene codes for an enzyme that is involved in the production of cholesterol. People who have SLOS are unable to make enough cholesterol to support normal growth and development.
Facial features because of SLOS?
microcephaly, drooping eyelid (ptosis), broad nasal bridge, upturned nose, undersized jaw (micrognathia), cleft palate
Limb anomalies becaose of SLOS?
short thumbs, polydactyly, syndactyly of the second and third toes (partial or completely united)
